Conference 2016

Conference 2016:

From Drug Discovery to Health Outcomes: Population to Patient

May 31 - June 3, 2016 River Rock Resort, Richmond, BC Canada

A joint conference of:

Canadian Society for Pharmaceutical Sciences Canadian Chapter of Controlled Release Society

Conference Chair: Frank Abbott, University of British Columbia, Vancouver, BC

Conference Organizing Committee: Michael Coughtrie (UBC), Jason Crawford (Centre for Drug Research & Development), David Kwok (BRI Biopharmaceutical Research Inc.), Shyh-Dar Li (UBC), Larry Lynd (UBC), Corey Nislow (UBC), Simon Pimstone (Xenon Pharmaceuticals Inc.), Robert Young (Simon Fraser University)

Staff: Bev Berekoff Barbara Scollick

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Conference Program

TUESDAY, MAY 31, 2016

8:00 AM Registration

9:00 - 5:00 Industry Day: Innovation and Management of Modern Pharmaceuticals (Whistler Ballroom B)

9:00 - 10:00 PLENARY 1: Carolyn Buser-Doepner, GSK New Trends in Pharma-Academia Collaborations for Drug Discovery Chair: Amyn Sayani, GSK SPONSORED BY: COLORCON 10:00-10:15 Refreshment and networking break Showcasing Drug Discovery Companies 10:15 - Chair: Jason Crawford, CDRD 11:00 Robin Sherrington, Xenon Pharmaceuticals Human Channelopathies: Providing Key Insights Into Drug Development Ernie McEachern, Alectos Therapeutics Alectos Therapeutics: Targeted Innovation in Preclinical Drug Discovery Novel Delivery Technologies for Therapeutics 11:00 - Chair: Pieter Cullis, UBC 12:30 John Babcook, Zymeworks Inc. Zymelink™ - Next Generation Drug Conjugates James Taylor, Precision Nanosystems The NanoAssemblr Platform: Microfluidic-based Manufacture of Nanomedicines from uLs to 10s L Michael Hope, Acuitas Therapeutics A Lipid Nanoparticle Platform to Enable mRNA Therapeutics 12:30 - 1:30 Lunch break and networking

1:30 - 2:30 Pharma at the Forefront in Drug Discovery Chair: Robert Young, SFU Jennifer Yearley, Merck Research Labs Translational Biology in the IO Space - Patient Response, Combination Therapies, New Approaches Anne Fourie, Janssen Pharmaceutical Research & Development Psoriasis - From Transformational Treatments to Cure and Interception 2:30 - 3:00 Refreshment and networking break New Commercialization Strategies, Regulatory Challenges, Big Data Issues 3:00 - 4:30 Chair: Jason Crawford, CDRD David Main, Aquinox, & Chair BIOTECanada New Commercialization Strategies Farzad Ali, Pfizer Access to New Medicines, Do Canadians Deserve Better? Paul Terry, PHEMI Health Systems Privacy, Governance & Innovation in the Era of Big Data

4:30 - 5:30 Closing Plenary: Chris Halyk, President, Janssen Inc. Are Innovative Medicines and our Life Sciences Industry at Risk in Canada? Chair: Catherine Lau, Janssen Inc. 5:30 - 7:00 Welcome Reception: CSPS, CC-CRS, AFPC SPONSORED BY JANSSEN INC.

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WEDNESDAY, JUNE 1 - MORNING SESSIONS

7:00 AM Registration and Poster Set-Up 7:30 - Trainee Mentoring Breakfast 9:00 9:00 - PLENARY LECTURE: Aaron Schimmer, Princess Margaret Cancer Centre 10:00 New Therapeutic Strategies to Target the Mitochondria in Leukemia Chair: Corey Nislow, UBC 10:00 - Refreshment Break: Posters, Exhibitors, and Networking (Theatre) 10:30 10:30 - SESSION 1: Special Populations SPONSORED BY: SANDOZ CANADA 12:00 Chair: Abby Collier, UBC SESSION 2: Regulatory Challenges and Opportunities

Chair: Fakhreddin Jamali, University of Alberta (Whistler Ballroom A) (Whistler Ballroom B) 10:30 Pediatric Development of Metabolizing Enzymes Regulatory Issues on the Determination of Abby Collier, University of British Columbia Bioequivalence for Modified-Release Drug Products with Multiphasic Concentration Profiles Laszlo Endrenyi, Faculty of Medicine, University of Toronto 11:00 PBPK Modelling and Simulation in Pediatric Drug Current Status of Decision-making for Biosimilars in Development Canada Andrea Edginton, University of Waterloo Agnes Klein, Biologics and Genetics Therapy Directorate, Health Canada 11:30 Developmental Pharmacology – ADME Consequences in Challenges in Ensuring Drug Product Quality in the Children Product Lifecycle Catherijne Knibbe, Universiteit Leiden Krishnan Tirunellai, Therapeutic Products Directorate, Health Canada

12:00 - GSK/CSPS Early Career Award Lecture 12:30 Mary De Vera, UBC Patient Engagement in Medication Adherence Research Chair: Larry Lynd, UBC

12:30 - Lunch break 2:00 Posters, Exhibitors, and Networking (Theatre)

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WEDNESDAY, JUNE 1 - AFTERNOON SESSIONS

2:30 - SESSION 3: Nanomedicines Become Personal: SESSION 4: Broaching the Fourth Hurdle: Getting 5:10 Opportunities and Challenges Drugs on the Formulary Co-Chairs: Shyh-Dar Li, UBC, and Amy Lee, Arbutus Chair: Larry Lynd, UBC Biopharma (Whistler Ballroom B) (Whistler Ballroom A) 2:30 Image-guided Focused Ultrasound for Targeted Delivery (2:30) Orphan Drugs-Catastrophic Drug Coverage of Drugs Fred Horne, Horne and Associates Kullervo Hynynen, Sunnybrook Res. Institute 3:00 Personalize Nanomedicines by Developing (2:45) Developing Specialty Drugs for a Conditional Multifunctional Nanoparticles and Identifying Reimbursement Environment: Is Quicker Necessarily Therapeutic Biomarkers Better? Shyh-Dar Li, UBC Chris McCabe, University of Alberta

3:30 Refreshment Break: Posters, Exhibitors, and Networking (Theatre) 4:00 Porphysome Nanotechnology: Discovery and Road to (3:00) Perspectives from a Public Drug Plan on the Clinical Translation Challenges and Opportunities with Expensive Drugs for Gang Zheng, Ontario Cancer Institute Rare Diseases (EDRD) Eric Lun, B.C. Ministry of Health (3:15) The Complexity in Making Reimbursement 4:30 TKM-Ebola and TKM-Ebola-Guinea: Rapid Re- Decisions around Expensive Drugs for Rare Diseases development of a Nucleic Acid Therapeutic in Response Doug Coyle, University of Ottawa to the West Africa Outbreak

Amy Lee, Arbutus Biopharma Corporation (4:00 - 5:00) Panel Discussion

5:00 - Oral Presentation from Posters: Oral Presentation from Posters: 5:15 Polymer-Lipid Based Nanomedicine of Synergistic Drug Preferences for Donating Money to Support Drug Combination for Improving Chemotherapy of Multidrug Development Research Projects in a Sample of Resistant Breast Cancer Canadian and U.S. Adults Rui Xue Zhang, University of Toronto Nick Dragojlovic, University of British Columbia

5:15 - Posters, Exhibitors, and Networking (Theatre) 6:00

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THURSDAY, JUNE 2 - MORNING SESSIONS

7:00 AM Registration and Poster Set-up

7:30 - Breakfast Lectures: Medical Marijuana 9:00 Chair: Frank Abbott, UBC Jonathan Page, UBC Chemical and Genomic Analysis of Cannabis Caroline MacCallum, Greenleaf Medical Clinic, & UBC Hospital Medical Clinic, Vancouver Medical Cannabis and Cannabinoids

9:00 - PLENARY LECTURE: Ivana Cecic , Genome BC 10:00 Genomics in Canada: From Knowledge Generation to Patient Outcomes Chair: Corey Nislow, UBC 10:00-- Refreshment Break: Posters, Exhibitors, and Networking (Theatre) 10:30 BREAK SPONSORED BY MSFHR

10:30 - SPONSORED BY: GENOME BC SESSION 6: Responsive Drug Delivery Systems 12:00 SESSION 5: Pharmacogenomics in the Clinic and Community Co-Chairs: Todd Hoare, McMaster University and Marc Gauthier, INRS Chair: Corey Nislow, UBC

(Whistler Ballroom A) (Whistler Ballroom B) (10:30-10:40) Trainee Presentation: Complete 10:30 Harnessing the Power of Synthetic Lethality: Regression of Xenograft Tumors upon Targeted Delivery Identifying and Targeting Dependencies in Cancer of Paclitaxel via Π-Π Stacking Stabilized Polymeric Lisa Belmont, Genentech Micelles Roy van der Meel, Utrecht University / UBC

Smart Automated Release, Because Drugs Don't Work in Patients who Don't Take Them Adah Almutairi, University of California, San Diego 11:00 Implementation of Pharmacogenomics for the Poly(2-oxazoline) Biomaterials Prevention of Severe Adverse Drug Reactions in Richard Hoogenboom, Ghent University, Belgium Pediatric Oncology Colin Ross, UBC and CFRI 11:30 UBC - GenomeBC - BCPhA Project "Bio-hybrid" Therapeutics Corey Nislow, UBC Marc Gauthier, Institut National de la Recherche Scientifique (INRS)

12:00 - CSPS Lifetime Achievement Award Lecture 12:30 Fakhreddin Jamali, University of Alberta Pharmaceutical Research and Development, Lessons Learned Chair: Raimar Loebenberg (Whistler Ballroom A) 12:30 - 12:30 - Annual Meetings: CSPS (Ballroom A) & CC-CRS (Ballroom B) 2:30 Lunch Break Posters, Exhibitors, and Networking (Theatre)

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THURSDAY, JUNE 2 - AFTERNOON SESSIONS

2:30 - SPONSORED BY: ZYMEWORKS SESSION 8: Health Sustainability SESSION 9: JOINT Session with 5:00 Evidence AFPC SESSION 7: Drug Targeting and Targeting Drugs Chair: Mark Harrison, UBC Chair: Simon Albon, UBC Chair: Robert Young, SFU (Whistler Ballroom A) (Whistler Ballroom B) (Fraser Room) 2:30 Targeted and Stimuli-sensitive Role of Patient Reported Outcome Integrating Pharmaceutical Combination siRNA/Drug Measures (PROMs) in the Ongoing Sciences into a Pharm D Curriculum Nanopreparations for Multidrug Evaluation of Treatment and Scott Singleton, The University of Resistant Cancer Reimbursement North Carolina at Chapel Hill Vladimir Torchilin, Northeastern Stirling Bryan, UBC/Centre for

University Clinical Epidemiology & Evaluation (C2E2) Roundtable Discussion 3:00 Advancements in Antibody Drug Patient Reported Outcome Conjugate Technology Measures (PROMs) and Patient Django Sussman, Seattle Genetics, Decision Making Inc. Mark Harrison, UBC

3:30 Refreshment Break: Posters, Exhibitors, and Networking (Theatre) BREAK SPONSORED BY MSFHR 4:00 Targeting of Solid Tumors with Bi- PROMs in Action: Changing Specific Antibodies and Bi-Specific Outpatient Asthma Care by drug Conjugates to Induce Novel Individualised Approach to Biologics and Drug-like Properties Medication Adherence David Poon, Zymeworks Mohsen Sadatsafavi, Faulty of Medicine, UBC 4:30 Design, Synthesis and Evaluation of Patient Reported Outcome Proms in Action: Changing Outpatient Asthma Care by Individualised Approach to Medication Adherence Novel Anabolic Bone Targeting Measures (PROMS): Do you Prodrugs for Treatment of Measure all that I Experience? Osteoporosis and Other Bone Cheryl Koehn, Arthritis Consumer Conditions Experts/JointHealth Bob Young, Simon Fraser University

5:00- Oral Presentation from Posters: Oral Presentation from Posters: 5:15 A First Report of an Intravesical How is Uncertainty in Risks and Therapy with Activity in a Muscle Benefits Presented in Patient Invasive Bladder Cancer Xenograft Decision Support Interventions? Model Madelaine Bell, UBC Clement Mugabe, CDRD 5:15- Posters, Exhibitors, and Networking (Theatre) 6:00 6:30 PM Conference Gala and Awards Dinner (Fraser Room) 6:30 Cash bar, 7:30 Dinner

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FRIDAY, JUNE 3 - MORNING SESSIONS

7:30 AM Registration

7:30 - SPONSORED BY AGILENT 9:00 Breakfast Lecture: Adam Rosebrock, University of Toronto Quantitative Mass-Spectrometry Metabolomics for Direct Biochemical Phenotyping Chair: Marcus Kim, Agilent

9:00 - SESSION 10: Analytical Innovation to Support SESSION 11: Protein and Peptide Delivery 12:00 Precision Medicine and Biologicals Development Co-Chairs: Brian Amsden, Queen's University, and Co-Chairs: Christoph Borchers, University of Victoria, and Larry Unsworth, University of Alberta David Kwok, BRI Biopharmaceutical Research Inc. (Whistler Ballroom A) (Whistler Ballroom B)

9:00 Distinguishing Leucine and Isoleucine Residues in De (9:00-9:10) Trainee Presentation: Development of a novo sequencing of mAbs using Nano LCMSn: A Segmented Intravaginal Ring for the Combination Potential to Replace Edman Degradation Delivery of Hydroxychloroquine and siRNA-encapsulated Dhanashri Bagal, Amgen Nanoparticles as a Novel Strategy for Preventing HIV Infection Yannick Traore, University of Manitoba

The Eyes Have It - Shifting Paradigms in the Delivery of Drugs to the Eye Heather Sheardown, McMaster University 9:30 ImmunoMALDI MS as a Diagnostic Tool for Primary Hollow Metallic Microneedles for Intradermal Delivery Aldosteronism Boris Stoeber, UBC Michael Chen, Jewish General Hospital, McGill

10:00 Refreshment and networking break 10:30 Understanding Biotransformations of a Therapeutic mAb New Strategies for Protein Delivery from Degradable and the Impact on Clinical PK Assay Development Microspheres Luna Liu, Genentech Brian Amsden, Queen's University 11:00 Multiplex and absolute protein quantitation by LC- Bioinspired and Nanotechnology-enabled Delivery of MRM/MS for clinical research Protein/Peptide Drugs for Diabetes and Diseases in the Christoph Borchers, University of Victoria Brain Xiao Yu (Shirley) Wu, University of Toronto

12:00 Conference Concludes

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Table of Contents

TUESDAY, MAY 31 INDUSTRY DAY: INNOVATION AND MANAGEMENT OF MODERN PHARMACEUTICALS

PLENARY LECTURE 1 New Trends in Pharma-Academia Collaborations for Drug Discovery ...... 18 Carolyn A. Buser-Doepner, Vice President of Discovery Partnerships with Academia, GlaxoSmithKline

SHOWCASING DRUG DISCOVERY COMPANIES Human Channelopathies: Providing Key Insights into Drug Development ...... 19 Robin Sherrington, PhD, Senior Vice President, Business & Corporate Development, Xenon Pharmaceuticals Inc. Alectos Therapeutics: Targeted Innovation in Preclinical Drug Discovery ...... 19 Ernest McEachern, PhD, President & CEO, Alectos Therapeutics

NOVEL DELIVERY TECHNOLOGIES FOR THERAPEUTICS Zymelink™ - Next Generation Drug Conjugates ...... 20 John Babcook, Senior VP, Discovery Research, Zymeworks Inc. The NanoAssemblr Platform: Microfluidic-based Manufacture of Nanomedicines from uLs to 10sL ...... 21 James Taylor, CEO and Co-Founder, Precision NanoSystems, Inc. A Lipid Nanoparticle Platform to Enable mRNA Therapeutics ...... 21 Michael Hope, Chief Scientific Officer, Acuitas Therapeutics

PHARMA AT THE FOREFRONT IN DRUG DISCOVERY Translational Biology in the IO Space - Patient Response, Combination Therapies, New Approaches ...... 22 Jennifer Yearley, Senior Principal Scientist and Director, Anatomic Pathology Group, Merck’s Biologics Discovery, Palo Alto, CA Psoriasis - From Transformational Treatments to Cure and Prevention ...... 22 Anne Fourie, Senior Director, Psoriasis Disease Area Stronghold Leader, Janssen Research & Development

NEW COMMERCIALIZATION STRATEGIES, REGULATORY CHALLENGES, BIG DATA ISSUES New Commercialization Strategies ...... 23 David J. Main, President & CEO, Aquinox Pharmaceuticals Inc., Vancouver, BC Access to New Medicines, Do Canadians Deserve Better? ...... 23 Farzad Ali, Director of Access for Oncology, Vaccines and Innovative Products, Pfizer Canada Privacy, Governance & Innovation in the Era of Big Data ...... 24 Paul Terry, CEO & CTO, PHEMI Systems, Vancouver, BC

PLENARY LECTURE 2 Are Innovative Medicines and our Life Sciences Industry at Risk in Canada? ...... 25 Chris Halyk, President, Janssen Inc. (Pharmaceutical Companies of Johnson & Johnson)

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WEDNESDAY, JUNE 1

PLENARY LECTURE 3 New Therapeutic Strategies to Target the Mitochondria in Leukemia ...... 26 Aaron D. Schimmer, MD, PhD, FRCPC, Princess Margaret Cancer Centre, Ontario Cancer Institute, University of Toronto, Toronto, Canada

SESSION 1: SPECIAL POPULATIONS Pediatric Development of Metabolizing Enzymes ...... 27 Abby Collier, Associate Professor of Pharmacology, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver PBPK Modelling and Simulation in Pediatric Drug Development ...... 27 Andrea N. Edginton, School of Pharmacy, University of Waterloo, Waterloo, ON, Canada Developmental Pharmacology – ADME Consequences in Children ...... 28 Catherijne A.J. Knibbe, Leiden Academic Centre for Drug Research, University of Leiden, Leiden, & Department of Clinical Pharmacy, St Antonius Hospital Nieuwegein and Utrecht, The Netherlands

SESSION 2: REGULATORY CHALLENGES AND OPPORTUNITIES Regulatory Issues on the Determination of Bioequivalence for Modified-Release Formulations with Multiphasic Concentration Profiles ...... 30 Laszlo Endrenyi, University of Toronto, ON Current Status of Decision-making for Biosimilars in Canada ...... 31 Agnes V. Klein, MD, DPH, Director, Centre for the Evaluation of Radiopahrmaceuticals and Biotherapeutic Products, Biologics and Genetic Therapies Directorate, Health Canada, Ottawa, ON Challenges in Ensuring Drug Product Quality in the Product Lifecycle ...... 31 Krishnan Tirunellai, Ph.D., Senior Scientific Advisor, Bureau of Pharmaceutical Sciences, Therapeutic Products Directorate, Health Canada, Ottawa, ON GSK/CSPS EARLY CAREER AWARD LECTURE Patient Engagement in Medication Adherence Research ...... 33 Mary De Vera, Assistant Professor, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver

SESSION 3: NANOMEDICINES BECOME PERSONAL: OPPORTUNITIES AND CHALLENGES Image-guided Focused Ultrasound for Targeted Delivery of Drugs ...... 34 Kullervo Hynynen, Sunnybrook Research Institute Personalize Nanomedicines by Developing Multifunctional Nanoparticles and Identifying Therapeutic Biomarkers ...... 34 Shyh-Dar Li, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC. Porphysome Nanotechnology: Discovery and Road to Clinical Translation ...... 35 Gang Zheng, Princess Margaret Cancer Centre and University of Toronto, Toronto, ON

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TKM-Ebola and TKM-Ebola-Guinea: Rapid Re-development of a Nucleic Acid Therapeutic in Response to the West Africa Outbreak ...... 35 Amy Lee, Arbutus Biopharma Corporation, Burnaby, BC, Canada Selected Abstract for Oral Presentation Polymer-Lipid Based Nanomedicine of Synergistic Drug Combination for Improving Chemotherapy of Multidrug Resistant Breast Cancer (Abstract # 85) ...... 36 Rui Xue Zhang, University of Toronto

SESSION 4: BROACHING THE FOURTH HURDLE: GETTING DRUGS ON THE FORMULARY Orphan Drugs - Catastrophic Drug Coverage ...... 37 Fred Horne, MBA, Adjunct Professor, School of Public Health, University of Alberta; Alberta Minister of Health, 2011-2014 Developing Specialty Drugs for a Conditional Reimbursement Environment: Is Quicker Necessarily Better? ...... 37 Christopher McCabe, PhD, Department of Emergency Medicine, Faculty of Medicine and Dentistry, University of Alberta Perspectives from a Public Drug Plan on the Challenges and Opportunities with Expensive Drugs for Rare Diseases (EDRD) ...... 38 Eric Lun, PharmD, ACPR, BSc. Pharm, B.Sc., Executive Director, Drug Intelligence and Optimization, Medical Beneficiary & Pharmaceutical Services Division, BC Ministry of Health The Complexity in Making Reimbursement Decisions around Expensive Drugs for Rare Diseases ...... 38 Doug Coyle, Professor, Department of Epidemiology and Community Medicine at the University of Ottawa Selected Abstract for Oral Presentation Preferences for Donating Money to Support Drug Development Research Projects in a Sample of Canadian and U.S. Adults ...... 39 Nick Dragojlovic, University of British Columbia

THURSDAY, JUNE 2

BREAKFAST SESSION: MEDICAL MARIJUANA Chemical and Genomic Analysis of Cannabis ...... 40 Jonathan Page, PhD, Anandia Labs Inc., Vancouver, and Botany Department, University of British Columbia, Vancouver BC, Canada Medical Cannabis and Cannabinoids ...... 40 Caroline MacCallum, Internal Medicine, UBC Hospital, and Bone Marrow Transplant Ward, VGH

PLENARY LECTURE 4 Genomics in Canada: From Knowledge Generation to Patient Outcomes ...... 41 Ivana Cecic, Health Sector Manager, Genome British Columbia

SESSION 5: PHARMACOGENOMICS IN THE CLINIC AND COMMUNITY Harnessing the Power of Synthetic Lethality: Identifying and Targeting Dependencies in Cancer ...... 42 Lisa Belmont, Genentech, Inc., South San Francisco, CA

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Implementation of Pharmacogenomics for the Prevention of Severe Adverse Drug Reactions in Pediatric Oncology ...... 43 Colin Ross, Assistant Professor of Pharmaco-genomics, Faculty of Pharmaceutical Sciences, University of British Columbia; Scientist, Child and Family Research Institute (CFRI), BC Children’s Hospital, Vancouver UBC - GenomeBC - BCPhA Project ...... 43 Corey Nislow, Associate Professor, Faculty of Pharmaceutical Sciences, Director of the UBC Sequencing Centre, and Tier 1 Canada Research Chair, UBC

SESSION 6: RESPONSIVE DRUG DELIVERY SYSTEMS Selected Abstract for Oral Presentation Complete Regression of Xenograft Tumors upon Targeted Delivery of Paclitaxel via Π-Π Stacking Stabilized Polymeric Micelles (Abstract #30) ...... 45 Roy van der Meel, Utrecht University / UBC Smart Automated Release, Because Drugs Don't Work in Patients who Don't Take Them ...... 45 Adah Almutairi, University of California, San Diego Poly(2-oxazoline) Biomaterials ...... 45 Richard Hoogenboom, Supramolecular Chemistry Group, Department of Organic and Macromolecular Chemistry, Ghent University, Krijgslaan, Ghent, Belgium "Bio-hybrid" Therapeutics ...... 45 Marc A. Gauthier, Institut National de la Recherche Scientifique, Varennes, QC, Canada CSPS AWARD OF LEADERSHIP IN CANADIAN PHARMACEUTICAL SCIENCES LECTURE Pharmaceutical Research and Development, Lessons Learned ...... 47 Fakhreddin Jamali, Professor, Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB

SESSION 7: DRUG TARGETING AND TARGETING DRUGS Targeted and Stimuli-sensitive Combination siRNA/Drug Nanopreparations for Multidrug Resistant Cancer ...... 48 Vladimir Torchilin, Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston, MA, USA Advancements in Antibody Drug Conjugate Technology...... 49 Django Sussman, Ph.D., Seattle Genetics, Inc., Bothell, WA Targeting of Solid Tumors with Bi-Specific Antibodies and Bi-Specific drug Conjugates to Induce Novel Biologies and Drug-like Properties ...... 49 David Poon, PhD, Executive Director for External R&D and Alliances, Zymeworks, Vancouver, BC Design, Synthesis and Evaluation of Novel Anabolic Bone Targeting Prodrugs for Treatment of Osteoporosis and Other Bone Conditions ...... 50 Robert N. Young, Department of Chemistry, Simon Fraser University, Burnaby, BC, Canada Selected Abstract for Oral Presentation A First Report of an Intravesical Therapy with Activity in a Muscle Invasive Bladder Cancer Xenograft Model (Abstract # 83) ...... 50 Clement Mugabe, CDRD

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SESSION 8: HEALTH SUSTAINABILITY EVIDENCE Role of Patient Reported Outcome Measures (PROMs) in the Ongoing Evaluation of Treatment and Reimbursement ...... 51 Stirling Bryan, Professor, School of Population & Public Health, and Director, Centre for Clinical Epidemiology & Evaluation (C2E2), UBC Patient Reported Outcome Measures (PROMs) and Patient Decision Making...... 51 Mark Harrison, Assistant Professor, Faculty of Pharmaceutical Sciences, University of British Columbia PROMs in Action: Changing Outpatient Asthma Care by Individualised Approach to Medication Adherence .....52 Mohsen Sadatsafavi, Academic Health Economist and Outcomes Researcher, Faulty of Medicine, UBC Patient Reported Outcome Measures (PROMs): Do you Measure all that I Experience? ...... 52 Cheryl L. Koehn, Founder and President, Arthritis Consumer Experts Selected Abstract for Oral Presentation How is Uncertainty in Risks and Benefits Presented in Patient Decision Support Interventions? (Abstract # 64) .53 Madelaine Bell, UBC

SESSION 9: JOINT SESSION WITH AFPC Integrating Pharmaceutical Sciences into a Pharm D Curriculum ...... 54 Scott Singleton, Assoc. Professor, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill

FRIDAY, JUNE 3

BREAKFAST LECTURE Quantitative Mass-Spectrometry Metabolomics for Direct Biochemical Phenotyping ...... 55 Adam Rosebrock, Assistant Professor, Donnelly Centre for Cellular and Biomolecular Research and Department of Molecular Genetics, University of Toronto

SESSION 10: ANALYTICAL INNOVATION TO SUPPORT PRECISION MEDICINE AND BIOLOGICALS DEVELOPMENT Distinguishing Leucine and Isoleucine Residues in De novo sequencing of mAbs using Nano LCMSn: A Potential to Replace Edman Degradation ...... 56 Dhanashri Bagal, Discovery Attribute Sciences, Amgen Inc., South San Francisco, California USA ImmunoMALDI MS as a Diagnostic Tool for Primary Aldosteronism ...... 56 Michael Chen MD MSc, McGill University, Department of Diagnostic Medicine, Jewish General Hospital, Montreal, Quebec Understanding Biotransformations of a Therapeutic mAb and the Impact on Clinical PK Assay Development ....57 Luna Liu, Jenny Li, Mauricio Maia, Mary Mathieu, Ihsan Nijem, Rebecca Elliott, Surinder Kaur, and Keyang Xu, Genentech, Inc., South San Francisco, CA Multiplexed Absolute Protein Quantitation by LC/MRM-MS for Clinical Research ...... 58 Christoph H. Borchers, University of Victoria - Genome BC Proteomics Centre and Dept. of Biochemistry and Microbiology, University of Victoria, BC Canada

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SESSION 11: PROTEIN AND PEPTIDE DELIVERY Selected Abstract for Oral Presentation Development of a Segmented Intravaginal Ring for the Combination Delivery of Hydroxychloroquine and siRNA-encapsulated Nanoparticles as a Novel Strategy for Preventing HIV Infection (Abstract #33) ...... 59 Yannick Traore, University of Manitoba The Eyes Have It - Shifting Paradigms in the Delivery of Drugs to the Eye ...... 59 Heather Sheardown, Professor, Department of Chemical Engineering, Faculty of Engineering. McMaster University, Hamilton ON Canada Hollow Metallic Microneedles for Intradermal Delivery ...... 60 Boris Stoeber, Department of Mechanical Engineering and Department of Electrical and Computer Engineering, The University of British Columbia, Vancouver, Canada New Strategies for Protein Delivery from Degradable Microspheres ...... 60 Brian Amsden, Professor, Department of Chemical Engineering at Queen’s University Bioinspired and Nanotechnology-Enabled Protein/Peptide Drug Delivery for Diabetes & Diseases in the Brain ..61 Xiao Yu (Shirley) Wu, PhD, FAAPS, Director of Advanced Pharmaceutics & Drug Delivery Laboratory, Leslie Dan Faculty of Faculty of Pharmacy, University of Toronto, Ontario

POSTER SESSION 1 - WEDNESDAY, JUNE 1 CSPS AND CC-CRS POSTERS

Biomedical Sciences 1. Can HIF-1α Silencing Overcome Hypoxia Induced Conversion of Triple Negative Breast Cancer to More Tumorigenic and Drug Resistant Phenotype? ...... 63 2. Replacement of Threonine with Alanine at Position 94 Amino Acid (T94A) of Rat Liver Fatty Acid Binding Protein by Site-Directed Mutagenesis ...... 63 3. Tyrosine Kinase Inhibitors Decrease Molecular Biomarkers of Fibrosis in Activated Hepatic Stellate Cells in vitro ...... 64 4. Zirconium-89 Labeled Gene Delivery Nanoparticles as Theranostic Agents for Melanoma ...... 64 5. Disparate Effects of Resveratrol and Analogues (Pterostilbene and Gnetol) in the Spontaneously Hypertensive Heart Failure (SHHF) Rat ...... 65 6. Characterization of Low Affinity Folate Transporters at the Blood-Brain-Barrier ...... 66 7. Demystifying Molecular and Cellular Mechanisms for Identifying Druggable Targets within Breast Cancer Cell Lines Using Newer Tyrosine Kinase Inhibitors ...... 66 8. Characterizing the Molecular Signaling Pathways in the Cerebral Arteries of Stroke-prone Spontaneously Hypertensive Rats (SHRsp) Before and After Stroke ...... 67 9. Effects of a Binge Drinking Ethanol Administration Protocol on the Long-term Motor Function and Cerebellar Physiology of Adolescent Rats ...... 67 10. Chemical Analysis and Neurobiological Effects of Newfoundland Wild Blueberries ...... 68 11. Cobalt (III) Complexes as Pro-drugs for Cancer Therapy ...... 68 12. Identification of the Mechanism of Action of Chemical Probes Against the Key Autophagy Enzyme ATG4B . 69 13. Long-term Adipose Tissue Preservation by Oxygen Delivery ...... 69

Clinical Sciences & Pharmacy Practice 14. Ethnicity and Natural Health Products Usage: Perceptions, Safety, and Pharmacoeconomics ...... 70 15. A Comparative Risk of Cardiovascular Events between Incident SSRI and SNRI Use: A Population-based Study ...... 70 16. A Safety Evaluation of Flaxseed Lignan Supplementation in Healthy Older Adults Following 6 Months of

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Once Daily Oral Administration ...... 71 17. A Systematic Review and Bayesian Network Meta Analysis (NMA) to Indirectly Compare the Efficacy of the Subsequent Entry Biologic (SEB) CT-P13 to REMICADE® (infliximab) in Patients with Crohn’s Disease (CD) ...... 71

Drug Delivery & Pharmaceutical Technology 18. In vivo Precipitation of Poorly Soluble Drugs from Lipid Based Formulations ...... 72 19. Investigation of CD205 Targeted PLGA Nanoparticles to Enhance Antigen Specific Immune responses .....72 20. Multi-location Multiple Stimuli-Responsive Degradation: A New Strategy for Accelerated Drug Release and Cancer Therapy ...... 73 21. In Vitro and In Vivo Characterization of Tabletted Spray-Congealed Lipid Microparticles for Extended Release of Vildagliptin ...... 74 22. Novel Application of siRNA-PEI Encapsulated Nanoparticles in Preventing Vaginal Infection of Chlamydia Trachomatis via PDGFR- β Knockdown and Autophagy Induction ...... 74 23. Synthesis of a Gemcitabine Prodrug for Remote Loading into Liposomes and Improved Therapeutic Effect . 75 24. Stable Encapsulation of Poorly Water-Soluble Drugs into Lipid Nanoparticles for Drug Delivery ...... 75 25. Nanoscale Reaction Vessels Designed for Synthesis of Copper-drug Complexes Suitable for Preclinical Development ...... 76 26. Mechanism of Low Density Lipoprotein Packaged Docosahexaenoic Acid Induced Toxicity of Hepatic Cancer Stem Cells and Mature Cancer Cells ...... 76 27. Eutectic Solid Form of Irbesartan-Syringic acid: Mechanistic Evaluation of Thermodynamic Properties, Solid State Characterization and In Vivo Studies ...... 77 28. Microfluidics-Based Manufacture of Size-Tunable Liposomes for the Delivery of Small Molecule Therapeutics ...... 77 29. Microfluidics-based Manufacture of RNA-Lipid Nanoparticles as Potent Delivery Vectors for Manipulating Gene Expression In Vitro and In Vivo ...... 78 30. Complete Regression of Xenograft Tumors upon Targeted Delivery of Paclitaxel via Π-Π Stacking Stabilized Polymeric Micelles ...... 78 31. Development of a Stable Liposomal Isotretinoin for Drug Delivery ...... 79 32. Intratumoral Penetration by a Nanoparticle of Podophyllotoxin on Tumor Spheroids and In vivo Tumor Models ...... 80 33. Development of a Segmented Intravaginal Ring for the Combination Delivery of Hydroxychloroquine and siRNA-encapsulated Nanoparticles as a Novel Strategy for Preventing HIV Infection ...... 80 34. Topical Nanoformulation for the Combination Delivery of Peptides for Accelerated Wound Healing and Synergistic Antibacterial Activity ...... 81 35. Poly (oligoethylene glycol methacrylate)-block-poly (D, L-lactide)-based Nanoparticles as Versatile Hydrophobic Drug Delivery Vehicles ...... 81 36. Polymeric Micelles for Targeted Delivery of Diclofenac and its Ethyl Ester Derivative in Inflammation .....82 37. Modification of Polymeric Micellar siRNA Delivery Systems with Breast Tumor Selective Peptide Ligands: Towards Development of Breast Tumor Targeted siRNA Nano-delivery Systems ...... 82 38. The Effect of MCL-1 Down Regulation on the Sensitization of Breast Cancer Cells to Doxorubicin and Caelyx® ...... 83 39. STK-01 a Novel Intravesical Therapy for Non-muscle Invasive Bladder Cancer ...... 83

Pharmaceutical & Analytical Chemistry 40. Simultaneous Determination of Oxybenzone, Octocrylene, Avobenzone, Octinoxate, Homosalate and Octisalate in Human Sunscreen Lotion by High-performance Liquid Chromatography with Ultraviolet Detection ...... 84 41. Histone Lysine Methyltransferase Inhibitors Decrease HOXA9 Expression and Induce Global Changes in Histone Post-translational Modifications ...... 84 42. Synthesis of Poly(ADP-ribose) Polymerase (PARP) Inhibitors (Phenanthridinones): The Application of Flow Chemistry Techniques in Medicinal Chemistry Programs ...... 85

14s | CSPS/CC-CRS Conference 2016, Vancouver, BC, Canada

43. Testicular Cytochrome P450 (CYP) Enzyme Expression Suppression by Phytoestrogen in Adult Male Rats . 86 44. In Vitro Bioactivation of Cyclic Phenol Phosphate Analogues as Potential Inhibitors of Autotaxin ...... 86

Pharmacokinetics & Pharmacodynamics 45. Tetrahydrocurcumin: Pharmacology and Bioavialability and Differential Pharmacological Effects of Curcumin Anologues ...... 87 46. Toxicity and Mechanisms of Transport of a Novel Organometallic Au(III) Compound Compared to Cisplatin on Rat Kidney Tissue Slices ex vivo ...... 87 47. Pre-clinical Pharmacokinetic and Pharmacological Characterization of Liquiritigenin, a Chiral Flavonoid ..88 48. Effect of Isoproterenol on Catabolism of Adenosine and Adenosine 5-‘triphosphate in Systemic Blood in vivo ...... 88 49. Lamotrigine Metabolism by UDP-Glucuronosyltransferases, UGT1A4 and UGT2B7, and their Role in Pediatric Toxicity Through Inadequate Glucuronidation ...... 89 AFPC POSTER PRESENTATIONS - JUNE 1, 2016 ...... 90

POSTER SESSION 2 - THURSDAY, JUNE 2 CSPS AND CC-CRS POSTERS

Biomedical Sciences 50. Altered Cardiac Protein Expression of CYP2j in Mouse Models of Type I and Type II Diabetes ...... 93 51. Determining the Kinetic Parameters of SET7/9 Protein Lysine Methyltransferase ...... 93 52. Hypouricemic Effects of Aqueous Extract of Erding Granules in Potassium Oxonate-Induced Hyperuricemic Mice ...... 94 53. Compatibility Effects of Herb Composition in Reducing Uric Acid Level in Hyperuricemic Mice ...... 94 54. The Cytotoxic Effect of Sphingosine-1-phosphate Towards Human Breast Cancer Cells in vitro ...... 95 55. Structural Modeling of Voltage-gated Sodium Channels: Improving Molecular Diagnostics in Pediatric Epilepsies ...... 95 56. Preferences for Donating Money to Support Drug Development Research Projects in a Sample of Canadian and U.S. Adults ...... 96 57. FRET-labeled Self-assembled Nanoprobe for Rapid and Sensitive Detection of Postoperative Pancreatic Fistula ...... 96 58. Using Photo-labelled Analogues of Ivacaftor to Probe for the Binding Site on Mutant CFTR ...... 97 59. Expenditures Guided by the Concept of Essential Medicines in Brazil: The Case of the Fibrates ...... 97 60. Discovery of 2-(1H-Indol-3-yl)-quinolines as Novel Inhibitors of Androgen Receptor Binding Function 3 (BF3) ...... 98 61. Novel Antimicrobials Derived from Parasitic Nematodes ...... 98

Clinical Sciences & Pharmacy Practice 62. Co-prescription of Antipsychotic and Antiparkinson Medications: Adherence to Guidelines and the STOPP (Screening Tool of Older Persons’ Potentially Inappropriate Prescriptions) Criteria in Beneficiaries of the Nova Scotia Seniors’ Pharmacare Program ...... 99 63. An Evaluation of the Quality of iPhone Applications for Hypertension Self-Management ...... 100 64. How is Uncertainty in Risks and Benefits Presented in Patient Decision Support Interventions? ...... 100 65. Alcohol Misuse and Medical Cannabinoids Use: Interactions Clinical Toxicology Aspects ...... 101

Drug Delivery & Pharmaceutical Technology 66. Development of Antibody-modified Chitosan Nanoparticles for the Targeted Delivery of siRNA Across the Blood-brain Barrier as a Strategy for Inhibiting HIV Replication in Astrocytes ...... 102 67. Preclinical Efficacy Study of a Podophyllotoxin-carboxymethylcellulose Nanoparticles Against Orthotopic

From Drug Discovery to Health Outcomes: Population to Patient | 15s

and Metastatic Tumors ...... 102 68. Production of Size-Tunable PLGA Nanoparticle Drug Delivery Systems using Microfluidic Technology..103 69. Microfluidics-Based Seamless Manufacture of RNA-Lipid Nanoparticles from Discovery to Clinic ...... 103 70. Microfluidics-Based Platform for the Scale-up of Lipid Nanoparticles for Delivery of Nucleic Acid Therapeutics ...... 104 71. Lanthanide Compounds for the Treatment of Bone Density Disorders ...... 104 72. Topical Nifedipine for the Treatment of Raynaud’s Syndrome ...... 105 73. Evaluation of Carbopol 934P NF Microemulsion-Based Gel Formulations for Topical Drug Delivery of Diclofenac Sodium ...... 106 74. Isolation of Primary Murine Brain Endothelial Cells, Pericytes and Astrocytes ...... 106 75. Hydroxychloroquine Attenuated Vaginal Tissue Inflammation and T-cell Activation in vivo ...... 107 76. pH-Sensitive Nanomicrobicide for the Targeted Delivery of siRNA to Vaginal Mucosal CD4+ Immune Cells in a Mouse Model ...... 107 77. Thermo-reversible Gels Based on Triblock Copolymers of PEG and Functionalized Caprolactone: The Effect of Polymer Polydispersity on their Gelation Behaviour ...... 108 78. Derivation and Experimental Validation of Ion-Exchange Model for Loading Anionic Drugs into Cationic Polyacrylate Polymer Eudragit® RS/RL Films ...... 108 79. Nano-encapusaltion of Inhibitors of Polynucleotide Kinase/Phosphatase (PNKP) by Polymeric Micelles for Selective Sensitization of Cancer Cells to DNA Damage ...... 109 80. Development of Anti-CD20 Immuno-micelles for Active Drug Targeting to Hematological Cancer ...... 109 81. Delivering in situ-Gelling Hydrogels for Ophthalmic Drug Therapies Using a Microinjection Device ...... 110 82. A Gadolinium-Doxorubicin Nanocomplex as a Novel Targeted Drug-Delivery System ...... 110 83. First Report of an Intravesical Therapy with Activity in a Muscle Invasive Bladder Cancer Xenograft Model . 111 84. 120 Encapsulation of Docosahexaenoic Acid in Polymer-Lipid Hybrid Nanoparticles Enhance Efficacy of Co-delivered Synergistic Drug Combination in Multidrug Resistant Breast Cancer Cells ...... 112 85. Polymer-Lipid Based Nanomedicine of Synergistic Drug Combination for Improving Chemotherapy of Multidrug Resistant Breast Cancer...... 112 86. Controlled Delivery System for Highly Soluble Active Ingredients: The Case of Metformin ...... 113

Pharmaceutical & Analytical Chemistry 87. Hypoxia-Activated SN-38: Targeting Hypoxic Tumors ...... 113 88. Development and Validation of a Reverse-phase Liquid Chromatography Mass Spectrometry Method for the Stereoselective Determination of Hydroxyeicosatetraenoic Acids ...... 114 89. Targeting the Oncogenic FOXM1 Transcription Factor in Cancer Treatment ...... 114 90. Inhibition of Influenza A M2 Ion Channel by Novel, Non-cytotoxic Derivatives of Hexamethylene Amiloride ...... 115 91. Determination of Polyphenolic Content and Antioxidant Capacity of Wild Newfoundland Berries ...... 115

Pharmacokinetics & Pharmacodynamics 92. The Impact of Diet-induced Obesity on the Metabolism of Amiodarone to Desethylamiodarone ...... 116 93. Effect of Diet Induced Obesity on Dronedarone Microsomal Metabolism in the Rat ...... 117 94. Using Population PBPK Modelling to Explore Variability in Trastuzumab Pharmacokinetics ...... 117 95. Anti-cancer Stem Cell Effect and Pharmacokinetics of Composite Polymeric Micelles of Reparixin and Paclitaxel ...... 118 96. Optimization and Development of Novel Topical Intestinal Agonists of the Bile Acid Receptor TGR5 for Treatment of Diabetes Mellitus and Associated Metabolic Diseases...... 118 AFPC POSTER PRESENTATIONS - JUNE 2, 2016 ...... 120

INDEX ...... 122

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Speaker Abstracts

From Drug Discovery to Health Outcomes: Population to Patient | 17s

Tuesday, May 31 Industry Day: Innovation and Management of Modern Pharmaceuticals

Plenary Lecture 1

SPONSORED BY: GSK

Chair: Larry Lynd, University of British Columbia

Applying the Canadian Institute of Health Patient Engagement in Medication Adherence Research’s definition of “meaningful and active Research collaboration in conduct as well as knowledge translation”, I will highlight novel approaches to Mary De Vera, Assistant Professor, Faculty of engaging with patients in completed and current Pharmaceutical Sciences, University of British adherence research among patients with Columbia, Vancouver inflammatory chronic conditions.

Although disease treatment options are now better Mary De Vera than they have ever been, it remains a challenge to Dr. Mary De Vera is a pharmacoepidemiologist / ensure that patients follow and complete their health services researcher and an Assistant Professor treatment regimen. Medication non-adherence has at UBC’s Faculty of Pharmaceutical Sciences. She been declared by the World Health Organization as obtained an MSc and PhD from UBC’s School of an epidemic costing billions of dollars in wasted Population and Public Health and completed post- health care resources. However, research on doctoral fellowships at University of Montreal’s interventions to help patients better take their Faculty of Pharmaceutical Sciences and UBC’s medications has been inconsistent and disappointing, Faculty of Pharmaceutical Sciences. The theme of with the bulk of prior studies failing to explore Dr. De Vera’s research is “Medication Matters” and patient perspectives around medication taking and her goal is to improve outcomes of medication adherence interventions. taking in different patient populations. Her current As holder of the Professorship in Medication research interests are: 1) understanding medication Adherence at UBC’s Faculty of Pharmaceutical adherence at the population level and developing Sciences, my research focuses on quantifying the and testing targeted interventions; and 2) examining burden of non-adherence through population-based the use and impacts of arthritis medications among pharmacoepidemiologic studies as well as pregnant women with arthritis. She holds career addressing the problem of non-adherence through awards from The Arthritis Society and the Michael novel approaches to adherence interventions. A Smith Foundation for Health Research. particular interest is the importance of patient engagement in medication adherence research.

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Wednesday, June 1 SESSION 3: Nanomedicines Become Personal: Opportunities and Challenges

Chair: Shyh-Dar Li, UBC, and Amy Lee, Arbutus Biopharma

was Honorary President of the 2nd International Image-guided Focused Ultrasound for Targeted Symposium on MRI-guided Focused Ultrasound by Delivery of Drugs the Focused Ultrasound Foundation. He was named the J. Eugene Robinson Awardee by the Society of Kullervo Hynynen, Sunnybrook Research Institute Thermal Medicine, the William and Francis Fry Honorary Fellow by the International Society for [Abstract not available] Therapeutic Ultrasound and was awarded the Silver Medal by the Acoustical Society of America. Kullervo Hynynen Recently awarded the IEEE Rayleigh Award Dr. Hynynen received his Ph.D. from the University (highest honor for achievement within the UFFC of Aberdeen, United Kingdom. After completing his Society in the field of Ultrasonics). postdoctoral training in biomedical ultrasound also at the University of Aberdeen, he accepted a faculty position at the University of Arizona in 1984. He Personalize Nanomedicines by Developing joined the faculty at the Harvard Medical School, Multifunctional Nanoparticles and Identifying and Brigham and Women’s Hospital in Boston, MA Therapeutic Biomarkers 1993. There he reached the rank of full Professor, and founded and directed the Focused Ultrasound Shyh-Dar Li, Faculty of Pharmaceutical Sciences, Laboratory. In 2006 he moved to University of University of British Columbia, Vancouver, BC. Toronto where he led a $160 million effort to establish the Centre for Research in Image-Guided Nanomedicine involves packaging an active drug Therapeutics, a consortium between the Canadian into a nano-sized vehicle to enhance the drug government and Sunnybrook Hospital. He is delivery by improving the solubility, stability and currently the Director of Physical Sciences Platform targeting of the drug. Personalized medicine focuses at the Sunnybrook Research Institute and a Professor on precise therapeutics for individual patients, in the Department of Medical Biophysics and Cross thereby improving the efficacy and reducing the side Appointed Professor in Institute of Biomaterials & effects. Incorporating personalized approaches into Biomedical Engineering (IBBME) at University of nanomedicine is one of the recent research focuses Toronto, Toronto, Ontario, Canada. He holds a in this field. I will report the recent progress in my Canada Research Chair in Imaging Systems and lab developing personalized nanomedicines via the Image-Guided Therapy awarded by the Government strategies of non-invasive imaging and biomarker of Canada and leads the Centre for Research in identification. Image-Guided Therapeutics. Dr. Hynynen has published over 325 peer reviewed papers on basic Shyh-Dar Li and clinical research and has been awarded 16 Dr. Li is an Associate Professor at UBC Faculty of patents many of which have been licensed by Pharmaceutical Sciences. His research focuses on industry. He has been the recipient of numerous NIH developing innovative drug delivery systems to and other agency grant awards, private sector enhance cancer chemotherapy. Dr. Li’s research research contracts; served on study sections, program has been supported by CIHR. He has editorial boards, and has been extensively involved receive several research awards, including CSPS in commercializing ultrasound technology. He is a Early Career Award, CIHR New Investigator Fellow of the American Institute of Ultrasound in Award, AFPC New Investigator Award, and AAPS Medicine, the Acoustical Society of America, and New Investigator Award. ([email protected])

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Porphysome Nanotechnology: Discovery and Institute, he joined the University of Pennsylvania in Road to Clinical Translation 2001 as an Assistant Professor of Radiology. Since moving to Canada in 2006, his research has been Gang Zheng, Princess Margaret Cancer Centre and focused on developing clinically translatable University of Toronto, Toronto, ON technology platform to combat cancer. Dr. Zheng’s most significant contributions are his pioneering Porphysomes, self-assembled from porphyrin-lipid work on activatable photosensitizers for building blocks, are unique nanoparticles with photodynamic therapy and his discovery of intrinsic multimodal photonic properties. The high- porphysome nanotechnology that opens new density packing of porphyrin bilayers enables these frontiers in cancer imaging and therapy. The latter nanoparticles to absorb and convert light energy to was also named one of the “top 10 cancer heat with extremely high efficiency, making them breakthroughs of 2011” by the Canadian Cancer ideal candidates for photothermal therapy and Society. During the last 5 years, Dr. Zheng photoacoustic imaging. Upon nanostructure published 81 peer-reviewed papers, gave 79 invited disruption, fluorescence and photoreactivity of free lectures and had 4 issued US patents. Dr. Zheng is porphyrins are restored to enable low background an Associate Editor for the Bioconjugate Chemistry fluorescence imaging and activatable photodynamic since 2014 and was recently elected to the College therapy. Here, our recent porphysome translational of Fellows of the American Institute for Medical and efforts are summarized. We have validated Biological Engineering (AMIBE). porphysome’s multimodal theranostic utilities in different cancer types (prostate, ovarian, head & neck cancer, pancreatic and brain cancer), different TKM-Ebola and TKM-Ebola-Guinea: Rapid Re- tumor models (subcutaneous, orthotopic, development of a Nucleic Acid Therapeutic in chemically-induced and primary) as well as different Response to the West Africa Outbreak animal species (mice, hamsters and rabbits). It was founded that the preferential uptake of porphysome Amy Lee, Arbutus Biopharma Corporation, in tumors versus adjacent normal tissues is well Burnaby, BC, Canada preserved across different tumor models. In addition, compared with any other photonic nanomaterials, TKM-Ebola was developed as a RNA interference porphysomes have considerably lower translational (RNAi) post-exposure therapeutic for Ebola hurdles owing to their a) simple two-step synthesis, Hemorrhagic Fever Virus (HFV) infections based on b) robust scale up following proven liposome a proprietary lipid nanoparticle (LNP) nucleic acid technology, c) extremely low systemic toxicity, and delivery platform. LNP are readily adapted for the d) proven biodegradable in vivo. Further, delivery of any nucleic acid molecule and have been porphysome can directly chelate radioisotope shown to be effective for a number of therapeutic copper-64 to enable quantitative and noninvasive applications: to date, nine LNP-based products have tracking of their in vivo fate via PET imaging. entered clinical trials. Ebola virus (EBOV) is Together, the simple yet intrinsic multimodal nature responsible for periodic episodes of haemorrhagic of porphysomes not only confers high potential for fever in Central Africa that produce severe disease clinical translation but also represents a novel and up to 90% mortality in humans, and has been principle for designing multifunctional identified as a weaponizable biological threat. nanoparticles. Developed in conjunction with the US Department of Defense, TKM-Ebola utilizes LNP- Gang Zheng encapsulated siRNA targeting mRNA transcripts Dr. Zheng is a Professor of Medical Biophysics, coding for essential viral components EBOV RNA Biomedical Engineering and Pharmaceutical polymerase L protein and viral protein VP35. TKM- Sciences at the University of Toronto, a Senior Ebola has undergone testing in a Phase 1 clinical Scientist, the Joey and Toby Tanenbaum/Brazilian trial, and was also used to treat Ebola-infected Ball Chair in Prostate Cancer Research at the subjects under the FDA compassionate use program Princess Margaret Cancer Center. He received his in the United States. PhD in 1999 from SUNY Buffalo in Medicinal The original TKM-Ebola product targets EBOV Chemistry. Following two year postdoctoral training variants from Central Africa, but it soon became in photodynamic therapy at the Roswell Park Cancer clear that the recent West African outbreak differed

From Drug Discovery to Health Outcomes: Population to Patient | 35s

not only in geography but also in the genetic identity Protiva Biotherapeutics) located near Vancouver, of the viral isolate involved. With viral genomic Canada. She has been involved in lipid nanoparticle information becoming available in April 2014 in the (LNP)-enabled nucleic acid drug discovery and form of viral sequence from just 3 patients (bolstered preclinical development for over 15 years across a by additional sequence data releases in the months to diverse range of therapeutic areas, including follow), we took advantage of the rapid response dyslipidemia, oncology, alcohol dependence, and nature of the LNP platform technology to develop a filovirus (Ebola, Marburg) infection. Career modified TKM-Ebola product to specifically address highlights have included the 2009 first-in-human the West Africa outbreak. This involved adjustment clinical trial for the lipid nanoparticle technology of 3 nucleotide positions across the two siRNA platform, wherein the particles were designed to components comprising the active drug moiety and deliver apolipoprotein B-targeting short interfering laboratory verification of pharmacology activity. RNA (siRNA) to the liver for the treatment of The streamlined manufacturing process for LNP hypercholesterolemia, as well as participation in subsequently enabled expeditious manufacture of efforts to medically respond to the 2014 Ebola clinical-grade material. The West African product, outbreak in West Africa. Currently she oversees a TKM-Ebola-Guinea, has subsequently demonstrated team of scientists focusing on animal pharmacology 100% survival in rhesus macaques and was selected modeling and nucleic acid drug discovery for for a controlled clinical trial in West Africa in Arbutus Biopharma's portfolio of RNA interference collaboration with the World Health Organization and small molecule drug candidates for the treatment (WHO), International Severe Acute Respiratory and of chronic Hepatitis B infection, which affects 400 Emerging Infecting Consortium (ISARIC), and the million people worldwide. Amy is an alumna of the Wellcome Trust. University of British Columbia’s Department of In this presentation, we discuss how TKM-Ebola Microbiology & Immunology. and TKM-Ebola-Guinea illustrate the ability of the siRNA-LNP drug technology platform to be quickly and effectively directed to respond to changes in a Selected Abstract for Oral Presentation drug target, whether that be variation in the target Polymer-Lipid Based Nanomedicine of over time or differences between patient Synergistic Drug Combination for Improving populations. Chemotherapy of Multidrug Resistant Breast

Cancer (Abstract # 85) Amy Lee

Amy Lee is a Senior Research Director at Arbutus Rui Xue Zhang, University of Toronto Biopharma (previously Tekmira Pharmaceuticals,

36s | CSPS/CC-CRS Conference 2016, Vancouver, BC, Canada

Wednesday, June 1 SESSION 4: Broaching the Fourth Hurdle: Getting Drugs on the Formulary

Chair: Larry Lynd, UBC

with which he has been associated include the Orphan Drugs - Catastrophic Drug Coverage Ontario Ministry of Health (District Health Council Program), Alberta Health (Director of Fred Horne, MBA, Adjunct Professor, School of Sustainability), the Conference Board of Canada and Public Health, University of Alberta; Alberta Mayo Clinic, among others. His work is currently Minister of Health, 2011-2014 focused on pan-Canadian strategies to support strategic health technology management; improved Ensuring equitable and affordable access to orphan access to and integration of palliative and end-of-life drugs is a continuing challenge for federal and care services; and pharmaceutical policy and provincial drug plans. While often discussed as a procurement. peripheral “cost driver” in the overall context of As Minister of Health, he was responsible for health care systems, rare diseases affect over 3 the province’s $18 billion health budget, the million Canadians. Viewed from this perspective, Ministry of Health and Alberta Health Services, the lack of an appropriate framework to support the province’s health delivery organization and the fifth development, evaluation, and reimbursement of largest employer in Canada. these drugs is arguably a significant public health Fred holds an MBA from Royal Roads issue that presents catastrophic implications for University and the Certificate in Dispute Resolution patients and families, and sub-optimal outcomes for from York University. He currently serves on the health systems. boards of the Canadian Physiotherapy Association As a former Minister of Health, Fred Horne will and the Canadian Frailty Network, among others. discuss these and related issues from a public policy and payer perspective. Drawing from the Alberta experience, Canada’s Rare Disease Strategy, and Developing Specialty Drugs for a Conditional observations about intergovernmental discussions Reimbursement Environment: Is Quicker and initiatives focused on reducing drug costs, he Necessarily Better? will make the case that a strategic pan-Canadian approach is required, and the time is now. Christopher McCabe, PhD, Department of Emergency Medicine, Faculty of Medicine and Fred Horne Dentistry, University of Alberta Fred Horne is a health policy consultant and served as Alberta’s Minister of Health from 2011-2014. A The translational process for specialty drugs may frequent speaker and panelist on health system appear to be in a constant state of change. Whilst issues in Canada, he is Principal of Horne and regulatory authorities such as the FDA, EMEA and Associates, Public Policy Consultants, and Adjunct Health Canada are lowering the evidentiary hurdles Professor at the School of Public Health, University through conditional licensing arrangements, health of Alberta. care payers are raising new hurdles, requiring Fred began his career in health policy over thirty different types of evidence and developing new years ago and has extensive experience in policy pathways to patient access and reimbursement. development and coordination, health system design Against this background, the science is moving and transformation, and stakeholder engagement. He toward increasingly targeted therapeutics and hence has worked extensively with provincial a larger proportion of all drugs falling into the governments, and research and stakeholder ‘Specialty Drug’ category and with correspondingly organizations in Canada and abroad. Organizations challenging prices. From a distance it can seem that

From Drug Discovery to Health Outcomes: Population to Patient | 37s

the regulators and reimbursement authorities are Eric Lun pulling in different directions. In his current role within Medical Beneficiary and In this talk I will discuss the rationale behind Pharmaceutical Services Division (MBPSD), Eric health care payers implementing conditional leads the Drug Intelligence and Optimization branch. reimbursement strategies and argue that, as The branch is responsible for determining which custodians of limited population health care drugs are included in the BC PharmaCare formulary resources it would be both unethical and through the national Common Drug Review (CDR- irresponsible to do otherwise. I will argue that these CADTH) process, the pan-Canadian Pharmaceutical schemes are the mechanism by which the payers can Alliance (pCPA) negotiation process, and the signal the value of high quality evidence to provincial Drug Benefit Council (DBC) review developers, and hence prevent patients from bearing process. The branch also is responsible for an excess proportion of the risk that is inherent in adjudicating drug funding requests through Special pharmaceutical research and development. Authority, supporting the optimal and appropriate I then will describe a framework for developers use of drugs in BC (e.g. supporting prescribing to think about the trade-offs between early guidelines and academic detailing), and leading regulatory approval and be subject to conditional other specialty programs and initiatives. reimbursement schemes. I will describe how Prior to joining MBPSD in 2007, Eric worked conditional reimbursement responses to immature with the Vancouver Coastal Health Authority as evidence may actually reduce the total market value Regional Coordinator, Medication Use Management. for a new technology and thus highlight the need for Eric has also worked as a financial research analyst developers to prospectively evaluate the impact on for the biotech and healthcare sector (TD Securities), revenues of alternative evidence development as a clinical pharmacist (Vancouver General strategies. Hospital), a Drug Use Evaluation pharmacist (University of Alberta Hospital), and a pharmacy [Bio not available] lecturer (University of Technology, Jamaica).

Perspectives from a Public Drug Plan on the The Complexity in Making Reimbursement Challenges and Opportunities with Expensive Decisions around Expensive Drugs for Rare Drugs for Rare Diseases (EDRD) Diseases

Eric Lun, PharmD, ACPR, BSc. Pharm, B.Sc., Doug Coyle, Professor, Department of Executive Director, Drug Intelligence and Epidemiology and Community Medicine at the Optimization, Medical Beneficiary & University of Ottawa Pharmaceutical Services Division, BC Ministry of Health In making funding decision relating to expensive drugs for rare diseases, both ethical and economics Drug plans, both public and private, face several concerns have been raised. In this talk, these issues complex challenges with expensive drugs for rare will be discussed with reference to recently available diseases. As a decision maker, he will review the products; eculizumab for the treatment of drug review process and what considerations are paroxysmal nocturnal hemoglobinuria (PNH) and included in making drug listing decisions. He will ivacaftor for the treatment of cystic fibrosis in also review the ongoing overall challenges with people with certain mutations. The presentation will overall drug plan management and the specific highlight the potential patient benefit associated with challenges and opportunities with EDRDS, such treatments and the associated opportunity costs. including the often limited clinical evidence and the The presentation will discuss issues relating to often extremely high costs set by the pharmaceutical identifiability, rule of rescue, innovation, equity and companies for these products. The opportunities to ethics with respect to funding decisions and thus address the challenges with EDRDs will not be highlight the underlying complexity facing decision easily resolved and will require a broad effort by all makers. involved stakeholders.

38s | CSPS/CC-CRS Conference 2016, Vancouver, BC, Canada

Doug Coyle Doug Coyle is a health economist and Professor in the Department of Epidemiology and Community Medicine at the University of Ottawa and at the Selected Abstract for Oral Presentation Health Economics Research Group at Brunel University where he obtained his PhD. Particular research interests include the handling of uncertainty Preferences for Donating Money to Support Drug and variability in economic evaluation and the Development Research Projects in a Sample of application to treatments for rare diseases. Doug is a Canadian and U.S. Adults current member of the Ontario Ministry of Health and Long Term Care's Committee to Evaluate Drugs Nick Dragojlovic, University of British Columbia and Drugs for Rare Diseases Working Group.

From Drug Discovery to Health Outcomes: Population to Patient | 39s

Thursday, June 2 Breakfast Session: Medical Marijuana

Chair: Frank Abbottd, UBC

based medicines using genomics and plant breeding. Chemical and Genomic Analysis of Cannabis He is also an Adjunct Professor in the Botany Department at the University of British Columbia. Jonathan Page, PhD, Anandia Labs Inc., Vancouver, and Botany Department, University of British Columbia, Vancouver BC, Canada Medical Cannabis and Cannabinoids

Cannabis sativa L. (marijuana, hemp; Cannabaceae) is Caroline MacCallum, Internal Medicine, UBC an ancient crop plant that produces nutritious seeds, Hospital, and Bone Marrow Transplant Ward, VGH high-quality fibre and bioactive cannabinoids, e.g. Delta-9-tetrahydrocannabinol (THC). We are using We will start by reviewing the endocannabinoid a combination of genomics and biochemistry to system, cannabinoids compounds, and their evidence, elucidate the cannabinoid metabolic pathway and to then shift clinically to focus on cannabinoid uses, better understand the genetic organization of the contraindications, routes and dosing, interactions, and genus Cannabis. A major experimental approach has side effects. We will discuss the pharmacists' role in been the use of EST and transcriptome data derived helping their patients navigate this process. from glandular trichomes, the specialized epidermal Dr. Caroline MacCallum structures that synthesize cannabinoids. We have Dr. MacCallum graduated from the University of successfully applied trichome-focused analysis to British Columbia Internal Medicine Residency identify three enzymes of the cannabinoid pathway: Program in 2013. She completed her Undergraduate hexanoyl-CoA synthetase, olivetolic acid cyclase and Medical training in 2009 and her Bachelors of Science an aromatic prenyltransferase. A draft assembly of the in Pharmacy in 2005 at Memorial University of ~820 Mbp genome from the marijuana strain Purple Newfoundland, where she was born and raised. Upon Kush, has opened up new avenues for gene discovery graduation, she practiced Pain & Addiction Medicine as shown by the identification of a novel cannabinoid at Vancouver General Hospital Complex Pain & synthase enzyme, cannabichromenic acid synthase. We Addiction Services, CHANGEpain Clinic, and at have recently used genotyping-by-sequencing (GBS) to Heartwood Addiction Program at BC Women’s analyze the genetic variation in 43 hemp and 81 Hospital. Currently she provides inpatient care on the marijuana accessions. GBS shows that hemp and Internal Medicine Ward at UBC Hospital and Bone marijuana are genetically distinct, and provides insight Marrow Transplant Ward at VGH; and outpatient care into the differentiation of marijuana into “Indica” and at BC Women’s Complex Chronic Disease Program “Sativa” groups. As cannabis emerges from the shadow She is also the medical director at Greenleaf of prohibition, genomics promises both to clarify its Medical Clinic; a cannabis clinic in Abbotsford, which evolutionary history and to accelerate the development authorizes legal Health Canada-approved medical of this valuable, multi-use crop. cannabis. Her cannabis research focus is in the Jonathan Page multimodal effects of cannabis on symptoms clusters; Jonathan has spent his career deciphering the genetic reducing polypharmacy, opioids and adverse drug and biochemical secrets of medicinal plants, including effects; and topical application of cannabis. the production of THC and other cannabinoids in In her private practice she offers group medical cannabis. He received his PhD from the University of visits in conjunction with allied health care British Columbia (1998), undertook postdoctoral professionals to provide patients with additional tools training in Germany (1998-2003) and directed a lab at to manage their complex pain. Groups include pain the National Research Council’s Plant Biotechnology neurosciences with focus on pacing, CBT, and Institute (2003-2013). Dr. Page co-led the Canadian mindfulness; therapeutic movement group; sleep and team that reported the first sequence of the cannabis nutrition groups as well as medicinal cannabis groups. genome and his work has helped elucidate the Dr. MacCallum is also passionate about student biochemical pathway leading to the major mentorship. She is the co-sponsor for the UBC Medical cannabinoids. He recently founded a biotechnology School Global Health Initiative on the Spiti India company, Anandia Labs, to develop new cannabis- Project.

40s | CSPS/CC-CRS Conference 2016, Vancouver, BC, Canada

Thursday, June 2 Plenary Lecture 4

Chair: Corey Nislow, UBC

on disease prevention instead of late treatment of Genomics in Canada: From Knowledge complex and rare diseases. Generation to Patient Outcomes After more than 10 years of investment in the field of genomics, Genome BC and the Canadian Ivana Cecic, Health Sector Manager, Genome Genomic Enterprise are now moving from projects British Columbia that generated knowledge about our genome and our genes, into projects that are focusing on With an ageing population and health care cost implementing innovative genomic technologies into increasingly rising, the human health sector is facing the healthcare system. Canada, and BC in particular, many important challenges around the world. There are starting to see now concrete projects where is a pressing need to increase innovation that could genomics is being implemented and integrated into lead to new and more efficacious medications in the health care system, leading to concrete order to address key global health issues such as socioeconomic impact and a more efficient health cancer and infectious diseases. Moreover, we have a care system. A series of concrete examples of the system that is mainly focusing on diagnosis and use and impact of genomics on key areas such as treatment of diseases instead of focusing on cancer, infectious diseases, pharmacogenomics and prevention and health. rare disease will be discussed in order to illustrate Thanks to the great technological advances that how the genomic revolution is changing the health have taken place after the sequence of the first care system in Canada and around the world. human genome in 2001, genomic (and all the “omic” technologies in general) tools are now offering Ivana Cecic concrete solutions to help improve the diagnosis and treatment of disease and also to promote a better [Bio not available] understanding of disease that could help focus more

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Thursday, June 2 SESSION 5: Pharmacogenomics in the Clinic and Community SPONSORED BY: GENOME BC

Chair: Corey Nislow, UBC

screens to identify additional targets in BRG1 Harnessing the Power of Synthetic Lethality: mutant cancer. Identifying and Targeting Dependencies in Cancer Lisa Belmont Dr. Belmont received her PhD from UCSF, where Lisa Belmont, Genentech, Inc., South San Francisco, she determined that increased microtubule CA catastrophe rate is the major mechanism governing changes microtubule dynamics during mitosis. She In the last decade we have begun to appreciate the went on to identify a novel protein that increases power and the challenges of personalized cancer microtubule catastrophe rate. She then moved to UC medicine. The successes have predominantly Berkeley where she demonstrated that actin filament focused on inhibiting pathways that are activated by destabilization is due to an opening of the mutation or amplification. However, a major nucleotide-binding cleft upon phosphate release after challenge of developing targeted cancer therapies ATP hydrolysis. Upon completion of post-doctoral lies in the observation that a large percentage of research, she joined a newly formed biotechnology oncogenic drivers are due to mutations that result in company and genetically engineered strains of loss of function (LOF). Strategies for targeting these Kluveromyces for direct conversion of cellulose to cancers are less direct and rely upon the fuel grade ethanol. After that she returned to her identification of cancer specific vulnerabilities that roots in the cell biology and spent five years at arise from LOF. Our research is focused on Cytokinetics Inc. working on target validation and strategies to target cancers with defects in the lead optimization for chemical inhibitors of mitotic SWI/SNF (BAF) complex, a chromatin-remodeling kinesins as experimental cancer therapeutics. In complex that repositions nucleosomes. The 2006, Dr. Belmont moved to Genentech, where she composition of SWI/SNF complexes varies by cell has led biology teams to support small molecule type, but all complexes contain one of two mutually inhibitor projects related to the cell cycle (mitotic exclusive ATP dependent helicases, SMARCA4 kinases), apoptosis (Bcl-2 family antagonists), tumor (BRG1) or SMARCA2 (BRM) that disrupt metabolism (NAMPT), and epigenetic regulators. nucleosome/DNA contacts to allow repositioning. Much of the work in these groups focused on the Large-scale cancer sequencing efforts have revealed identification of predictive biomarkers for that 20% of all cancers harbor a mutation in at least experimental therapeutics as part of a personalized one subunit of the SWI/SNF complex, including medicine initiative. The Bcl-2 antagonist, 10% of non-small cell lung cancers with mutations venetoclax, was recently approved for use in in BRG1. Loss of BRG1 renders the cancer cells Chronic Lymphocytic Leukemia (CLL) patients with dependent upon BRM for survival, making it an 17p deletion, a common deletion that removes the appealing drug target for BRG1 mutant cancers. tumor suppressor, p53. Her lab is currently working However, there are challenges to making a selective on identification of synthetic lethal interactions in small molecule inhibitor of BRM. As such, we are cancer to identify vulnerabilities created by loss of evaluating multiple approaches to targeting BRG1 tumor suppressors that can be targeted with small cancer. The approaches include novel strategies for molecule inhibitors. inhibiting BRM and running CRISPR/Cas9 dropout

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Implementation of Pharmacogenomics for the disorder of lipid metabolism, which recently became Prevention of Severe Adverse Drug Reactions in one of the first gene-based therapies to receive Pediatric Oncology regulatory approval. My research is now largely focused on the identification/ implementation of Colin Ross, Assistant Professor of Pharmaco- genetic factors of drug response to better guide safer genomics, Faculty of Pharmaceutical Sciences, and more effective individualized patient treatments. University of British Columbia; Scientist, Child and The debilitating and sometimes lethal consequences Family Research Institute (CFRI), BC Children’s of severe adverse drug reactions are a striking Hospital, Vancouver. problem in modern medicine. The consequences for patients who experience severe ADRs can be Adverse drug reactions (ADRs) account for an catastrophic. I helped establish the ‘Canadian alarming 7% of all hospital admissions and are Pharmacogenomics Network for Drug Safety’ ranked as a leading cause of death in the USA. The (CPNDS), a network of clinicians and researchers in Canadian Pharmacogenomics Network for Drug hospitals across Canada to identify patients that have Safety (CPNDS) was established to identify, report, suffered severe ADRs with the goal of developing and solve drug safety concerns in pediatrics. and implementing genotype-based predictive Pediatric oncology is especially constrained by the pharmacogenomic tests to help optimize individual problem of severe ADRs. drug treatment. As an example, anthracyclines are a class of highly effective chemotherapeutic widely used to treat childhood and adult cancers. The use of UBC - GenomeBC - BCPhA Project anthracyclines, however, is limited by the development of serious cardiotoxicity in some Corey Nislow, Associate Professor, Faculty of patients. Candidate gene studies have suggested a Pharmaceutical Sciences, Director of the UBC pharmacogenomic component to this severe adverse Sequencing Centre, and Tier 1 Canada Research drug reaction. We recently conducted a genome- Chair, UBC wide pharmacogenomic study of anthracycline- induced cardiotoxicity and performed exploratory In the year 2000 the human genome project mechanistic studies of an emergent prioritized gene, announced the completion of the first draft human RARG. Our studies indicate that RARG plays an DNA sequence, a 15 year project which cost $3 important role in the development of anthracycline- billion and enormous research investment. This induced cardiotoxicity. accomplishment, while extraordinary, failed to In a multidisciplinary collaboration (e.g., clinical deliver on many of the project’s promises. In pharmacology, pediatric oncology, cardiology, retrospect the reasons are obvious. The 3 billion pharmacogenetics) we have implemented a clinical letters of the human genome are in fact 99.5% research program to explore the use of identical between any two individuals- it is this pharmacogenomics as a tool for ADR mitigation in small fraction, approximately 3 million so-called pediatric oncology in BC. DNA variants that distinguish individuals and determine i) our susceptibility to disease ii) our Colin Ross unique physiology and cognitive capacities and iii) Colin Ross, BSc.h (UBC), MSc (Newcastle, UK), our response to hundreds of medication. Because the PhD (McMaster University), is an Assistant best way to define cause and effect requires very Professor of Pharmacogenomics, Faculty of high confidence correlations, in order to infer the Pharmaceutical Sciences, University of British effect of any single genetic variant on drug response, Columbia, and Scientist, Child and Family Research large numbers of sequenced human genomes are Institute (CFRI) at the BC Children’s Hospital in required. In the past three years the sequencing Vancouver. landscape has been transformed, and thousands of I grew up in the Penticton, B.C, and I am genomes from diverse populations have been married with two boys (aged 11 and 13). My collected and carefully annotated by our group and research seeks to integrate genetics with novel others. To use this information in practice, one needs strategies to improve the safety and effectiveness of a means to collect individual biological samples medications. For example, I developed a novel gene- (such as saliva), deliver them to a clinically certified delivery treatment for LPL Deficiency, a genetic sequencing laboratory and return that information

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(and ONLY that information) encoded within an University. Before joining UBC, Dr. Nislow was individual’s DNA sequence to tailor their medication associate professor at the University of Toronto. In and dose. Over the course of an 18 month the UBC Faculty of Pharmacy he is an Associate Community Pharmacogenomics project we Professor, Director of the UBC Sequencing Centre demonstrated that the logistics and infrastructure to and a Tier 1 Canada Research Chair. His work on deliver genomic information from patient to drug-gene and drug-environment interactions is pharmacist and back again is safe, reproducible and broad in scope, ranging from yeast to human and, as scalable. This project represents a unique blending part of an ongoing collaboration with NASA and of clinical research with pharmacy providers and Duke University, he has flown experiments on 4 patient engagement to realize the patient benefits of missions to the International Space Station. Nislow using cutting-edge Pharmacogenomics research to is Principal Investigator for the ‘Genomics for help patients. Precision Drug Therapy in Community Pharmacy’ project, which demonstrated that pharmacists are Corey Nislow well positioned to convey pharmacogenomics Corey Nislow completed his doctor of philosophy in information to their patients and their healthcare University of Colorado. He was an American Cancer team. He has 150 peer-reviewed publications and 6 Society fellow, group leader in three biotechnology issued patents. companies and senior genome scientist at Stanford

44s | CSPS/CC-CRS Conference 2016, Vancouver, BC, Canada

Thursday, June 2 SESSION 6: Responsive Drug Delivery Systems

Co-Chairs: Todd Hoare, McMaster University and Marc Gauthier, INRS

mass polymers for use in preparation of solid Selected Abstract for Oral Presentation dispersion as well as functional poly(2-oxazoline)s as biomaterials. Complete Regression of Xenograft Tumors upon Targeted Delivery of Paclitaxel via Π-Π Stacking Richard Hoogenboom Stabilized Polymeric Micelles (Abstract #30) Richard Hoogenboom was born in 1978 in Rotterdam (the Netherlands) and studied chemical Roy van der Meel, Utrecht University / UBC engineering at the Eindhoven University of Technology (the Netherlands). In 2005, he obtained Smart Automated Release, Because Drugs Don't his Ph.D. under the supervision of Ulrich S. Work in Patients who Don't Take Them Schubert and continued working as a project leader for the Dutch Polymer Institute. After postdoctoral Adah Almutairi, University of California, San Diego training at the RWTH Aachen with Prof. Martin Moeller and at the Radboud University Nijmegen [Abstract & Bio not available] with Prof. Roeland Nolte, he was appointed as associate professor at Ghent University in 2010 and in October 2014 he was promoted to full professor. Poly(2-oxazoline) Biomaterials His research interests include stimuli-responsive polymers, supramolecular polymers, and poly(2- Richard Hoogenboom, Supramolecular Chemistry oxazoline)s. He has published more than 260 Group, Department of Organic and Macromolecular refereed scientific articles and is associate editor for Chemistry, Ghent University, Krijgslaan, Ghent, European Polymer Journal and Australian Journal of Belgium. [email protected] Chemistry.

The living cationic ring-opening polymerization of 2-oxazolines has been studied in great detail since its "Bio-hybrid" Therapeutics discovery in 1966. The versatility of this Mi Liu1, Gregor Fuhrmann1, Pål Johansen2, Jean- polymerization method allows copolymerization of a 1 3 variety of 2-oxazoline monomers to give a range of Christophe Leroux , Marc A. Gauthier . 1Department of Chemistry Applied Biosciences, tunable polymer properties that enable, for example, 2 hydrophilic, hydrophobic, fluorophilic, as well as ETH Zurich; Department of Dermatology, University Hospital Zurich, Zurich, Switzerland; hard and soft materials. However, this class of 3 polymers was almost forgotten in the 1980s and EMT Research Center, Institut National de la 1990s because of the long reaction times and limited Recherche Scientifique, Varennes, QC, Canada application possibilities. In the new millennium, a revival of poly(2-oxazoline)s has arisen because of In comparison to neutral linear polymers, functional their potential use as biomaterials and and architecturally complex (i.e., nonlinear) thermoresponsive materials, as well as the easy polymers offer distinct opportunities for enhancing access to defined amphiphilic structures for the properties and performance of therapeutic (hierarchical) self-assembly. Recent developments proteins. However, understanding how to harness from our research that illustrate the potential of these parameters is challenging, and studies that poly(2-oxazoline)s will be discussed in this lecture, capitalize on them in vivo are scarce. This including the preparation of defined high-molar presentation will cover this important topic with emphasis on two types of therapeutic proteins: ones

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for which long circulation in the bloodstream is 2013, 23, 2007 desired, and ones for which retention and/or [2] Liu, Johansen, Zabel, Leroux, Gauthier. Nature stabilization in the gastrointestinal tract is desired. Communications, 2014, 5, 5526. We will first present how the modification of an [3] Fuhrmann, Grotzky, Lukić, Matoori, Yu, enzyme with a polymer of appropriate architecture Luciani, Walde, Schlüter, Gauthier, Leroux. Nature can impart exceptionally low immunogenicity (e.g., Chemistry, 2013, 5, 582 generation/recognition of antibodies in vivo), with a commensurably low loss of therapeutic activity.[1,2] Marc A. Gauthier Secondly, we will also discuss how the modification Prof. Marc A. Gauthier obtained his PhD in polymer of an enzyme with a polymer bearing appropriate chemistry at the Université de Montréal in 2007. functional groups can promote its stability (and thus Following a postdoc at the Swiss Federal Institute of therapeutic activity) at different locations in the Technology Lausanne (EPFL), he became a gastrointestinal tract. Furthermore, functional Research Associate at the Swiss Federal Institute of polymers that interact with mucin will be shown to Technology Zurich (ETHZ) in 2009. In 2013 he promote retention in the upper part of the joined the faculty of the Institut National de la gastrointestinal tract, and thus enhance the Recherche Scientifique (INRS) in Canada where his therapeutic activity of enzymes at this location.[3] work focuses on developing new types of dynamic Overall, the importance of the findings will be covalent bonds, designing therapeutic protein– framed with context to selected relevant diseases polymer conjugates, establishing new technologies that stand to benefit most from the presented for drug discovery, and investigating new concepts. opportunities for physically actuating therapeutic [1] Liu, Tirino, Radivojevic, Phillips, Gibson, bioconjugates Leroux, Gauthier. Advanced Functional Materials. .

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Thursday, June 2 CSPS Award of Leadership in Canadian Pharmaceutical Sciences Lecture

Chair: Raimar Loebenberg, University of Alberta

academic achievements and research, he has been Pharmaceutical Research and Development, appointed as a Fellow of the Canadian CSPS, the Lessons Learned American Association of Pharmaceutical Sciences, and the American College of Clinical Pharmacology. Fakhreddin Jamali, Professor, Faculty of Pharmacy He has received the Killam Professorship, McKeen and Pharmaceutical Sciences, University of Alberta, Cattell Memorial Award of the American College of Edmonton, AB Clinical Pharmacology, the McCalla Professorship of the University of Alberta, the McNeil Award of [No abstract] Association of Faculties of Pharmacy of Canada, and the CSPS Leadership Award. For his service to the Fakhreddin Jamali public, he has been honored with the Alberta Dr. Jamali (Doctor of Pharmacy, University of Centennial Medal and the Alberta Pharmacy Tehran; MSc, pharmaceutics and PhD, Centennial Award of Distinction. Dr. Jamali has pharmacokinetics, University of British Columbia) served as an expert witness as well as consultant is a professor at the Faculty of Pharmacy and and/or a member of the board of directors of many Pharmaceutical Sciences, University of Alberta. His pharmaceutical houses. He has been a member of the research interests include effect of Health Canada’s Expert Advisory Committee on pathophysiological changes on the action and Bioavailability and Bioequivalence, and the Expert disposition of drugs, stereochemical aspects of drugs Advisory Panel on Nonsteroidal Anti-inflammatory action and disposition, basic and clinical Drugs. He is the founding president of CSPS and pharmacology of anti-rheumatic, analgesic and editor of J. Pharm. & Pharm. Sci., first open access cardiovascular drugs, and toxicology of nonsteroidal journal in the field. He teaches pharmacokinetics and anti-inflammatory drugs. He has trained 39 PhDs has been involved in pharmacy curriculum and published over 220 refereed articles, mainly development. reporting original research (H-Score, 42). For his

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Thursday, June 2 SESSION 7: Drug Targeting and Targeting Drugs SPONSORED BY: ZYMEWORKS

Chair: Robert Young, Simon Fraser University

pH-, hypoxia-, or MMP2-sensitive bonds between Targeted and Stimuli-sensitive Combination different components of nanopreparations co- siRNA/Drug Nanopreparations for Multidrug loaded with siRNA and drugs, we were able to Resistant Cancer make the systems specifically delivering biologically active agents in tumors, which resulted Vladimir Torchilin, Center for Pharmaceutical in significantly improved therapeutic response. Biotechnology and Nanomedicine, Northeastern University, Boston, MA, USA Vladimir Torchilin Vladimir P. Torchilin is a University Distinguished Tumor therapy, especially in the case of multidrug Professor and Director, Center for Pharmaceutical resistant cancers, could be significantly enhanced Biotechnology and Nanomedicine, Northeastern by using siRNA down-regulating the production of University, Boston. He graduated from the proteins, which are involved in cancer cell Moscow University with MS in Chemistry, and resistance, such as Pgp or survivin. Even better obtained there his Ph.D. and D.Sc. in Polymer response could be achieved is such siRNA could be Chemistry and Chemistry of Physiologically delivered to tumors together with Active Compounds in 1971 and 1980, respectively. chemotherapeutic agent. This task is complicated In 1991, Dr. Torchilin joined MGH/Harvard by low stability of siRNA in biological Medical School as the Head of Chemistry Program, surrounding. Thus, the delivery system should Center for Imaging and Pharmaceutical Research, simultaneously protect siRNA from degradation. and Associate Professor of Radiology. Since 1998 We have developed several types of lipid-core Dr. Torchilin is with Northeastern University. He polymeric micelles based on PEG-phospholipid or was the Chair of the Department of Pharmaceutical PEI-phospholipid conjugates, which are Sciences in 1998-2008. His research interests biologically inert, demonstrate prolonged include liposomes, lipid-core micelles, biomedical circulation in the blood and can firmly bind non- polymers, drug delivery and targeting, modified or reversibly-modified siRNA. pharmaceutical nanocarriers, experimental cancer Additionally, these nanopreparations can be loaded immunology. He has published more than 350 into their lipidic core with poorly water soluble original papers (which received more than 30,000 chemotherapeutic agents, such as paclitaxel or citations), more than 150 reviews and book camptothecin. In experiments with cancer cell chapters, wrote and edited 10 books, including monolayers, cancer cell 3D spheroids, and in Immobilized Enzymes in Medicine, Targeted animals with implanted tumors, it was shown that Delivery of Imaging Agents, Liposomes, such co-loaded preparations can significantly Nanoparticulates as Pharmaceutical Carriers, down-regulate target proteins in cancer cells, Biomedical Aspects of Drug Targeting, and holds enhance drug activity, and reverse multidrug more than 40 patents. He is Editor-in-Chief of resistance. Current Drug Discovery Technologies, of Drug In order to specifically unload such Delivery, and of OpenNano and on the Editorial nanopreparations inside tumors, we made them Boards of many journals including Journal of sensitive to local tumor-specific stimuli, such as Controlled Release (Review Editor), Bioconjugate lowered pH, hypoxia, or overexpressed certain Chemistry, Advanced Drug Delivery Reviews, enzymes, such as matrix metalloproteases. Using Molecular Pharmaceutics. Among many awards,

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Professor Torchilin was the recipient of the 1982 Django Sussman Lenin Prize in Science and Technology (the Dr. Sussman leads antibody engineering efforts at highest award in the former USSR). He was Seattle Genetics as Director of Protein Sciences, elected as a Member of European Academy of focusing on improving the pharmacokinetics, Sciences. He is also a Fellow of American Institute efficacy and tolerability of antibody drug conjugates. of Medical and Biological Engineering, of Prior to joining Seattle Genetics, he was an American Association of Pharmaceutical Scientists American Cancer Society postdoctoral fellow at the (AAPS), and of the Controlled Release Society Fred Hutchinson Cancer Research Center where he (CRS), and received the 2005 Research studied the structure-function relationship in Achievements in Pharmaceutics and Drug Delivery endonucleases leading to rational and computational Award from the AAPS, 2007 Research redesigns for altered specificity. In 2000 he earned Achievements Award from the Pharmaceutical his Ph.D from the University of California – Santa Sciences World Congress, 2009 AAPS Journal Cruz in Molecular, Cellular and Developmental Award, 2009 International Journal of Biology where he solved the first crystal structure of Nanomedicine Distinguished Scientist Award, an RNA aptamer. He obtained his BS in Molecular 2010 CRS Founders Award, 2012 Alec Bangham Biology from the University of California – San Life Achievement Award, 2013 Journal of Drug Diego in 1995. Targeting Life Achievement Award, and 2013 Blaise Pascal Medal in Biomedicine from the European Academy of Sciences. In 2005-2006 he Targeting of Solid Tumors with Bi-Specific was a President of the Controlled Release Society. Antibodies and Bi-Specific drug Conjugates to In 2011, Times Higher Education ranked him Induce Novel Biologies and Drug-like Properties number 2 among top world scientists in pharmacology for the period of 2001-2010, and his David Poon, PhD, Executive Director for External H-index according to Google Scholar is 92 with R&D and Alliances, Zymeworks, Vancouver, BC more than 43,000 citations. His research was supported by more than $20 million he received as A robust, developable and manufacturable bi- grants from the government and industry over the specific platform will be discussed as the last 15 years. foundation to engineer novel anti-solid tumor antibodies. Unlike combination therapies, these bi- specifics demonstrate enhanced tumor decoration, Advancements in Antibody Drug Conjugate tumor diffusion and retention, internalization, and Technology effector functions. Supported with IND-enabling in vivo efficacy studies, Zymeworks’ lead bi-specific Django Sussman, Ph.D., Seattle Genetics, Inc., and bi-specific ADC programs will be presented. Bothell, WA David Poon The use of monoclonal antibodies for the delivery of David is the Executive Director for External R&D anticancer drugs to tumor cells has been the subject and Alliances and has been at Zymeworks for 8 of a great deal of investigation. The field has years. During this span, he held various positions advanced significantly with recent approvals of including overseeing all wet-lab operations and antibody-drug conjugates (ADCs) for the treatment made key contributions to the development of the of lymphomas and breast cancer. There are several Azymetric™ and AlbuCORE™ platforms. He aspects in antibody-drug conjugate (ADC) design currently oversees Zymeworks’ strategic that influence activity, safety, and specificity. This collaborations and its in- and out-licensing talk will present recent advances in ADC activities. David received his Ph.D. in Chemistry development relative to the antigen target, the from the University of British Columbia with a drug/linker combination, and the mode and focus on studying the structure-function multiplicity of drug/linker attachment to the relationship of enzymes using NMR spectroscopy. antibody delivery vehicle.

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Design, Synthesis and Evaluation of Novel Substances Naturelles in Gif-sur-Yvette, France Anabolic Bone Targeting Prodrugs for (1976-7) and from 1977 until 2006 worked in Treatment of Osteoporosis and Other Bone various capacities with Merck Frosst Canada & Co. Conditions including Vice-President and Head of the Medicinal Chemistry Department. Acting site head at the Robert N. Young, Gang Chen and Haibo Xie Merck Frosst Centre for Therapeutic Research Department of Chemistry, Simon Fraser University, (Montreal) and at MSD, Terlings Park Burnaby, BC, Canada Neurosciences Centre in the UK before taking early retirement in 2006. Dr. Young’s industrial career Prostaglandin E2 (PGE2) is known to stimulate bone focused on the design and synthesis of novel drugs growth in vivo through agonism at the EP4 receptor. for asthma, inflammation, osteoporosis and he is Potent and EP4-selective agonists have been most noted for his part in the discovery of the described but, like PGE2 itself, suffer from systemic asthma drug, SingulairTM and of the anti- side effects that limit their use as stand alone drugs. inflammatory drug ArcoxiaTM. We have designed and synthesized a number of Since 2007, Professor of Chemistry and Merck bone-targeting, slow release pro-drugs wherein the Frosst-B.C. Leadership Chair in Pharmaceutical EP4 agonists are conjugated with bone targeting Genomics, Bioinformatics and Drug Discovery in bisphosphonates (such as alendronic acid) through the Chemistry Department, Simon Fraser University. enzymatically cleavable linker elements. These Current research is focused on the design and agents are designed to be inactive in their own rights synthesis of novel pharmacological probes and and to bind to bone after systemic administration proof-of-concept molecules for the discovery of new and then slowly release the active bone growth drug targets. Active research programs include, stimulating EP4 agonist with half times of release on discovery of novel modulators of the androgen the order of 4-7 days. Some of these agents also receptor (for treatment of prostate cancer), inhibitors release the bone resorption inhibitor, alendronic acid is cellular “autophagy” (as anticancer therapy), through the local action of the enzymes such as molecular probes to define the mechanism of cystic cathepsin K (a protease which is released by fibrosis drugs and projects directed to improving osteoclasts .as part of the bone resorption process). bone health and treating osteoporosis. Author of Pro-drugs were synthesized in doubly radiolabeled more than 200 publications, review articles and form (with tritium on the EP4 moiety and C14 on patents. the linker element, in order to follow and quantify Selected Honours: Order of Canada (MC), the uptake, and release of the active agents. These Fellow of the Royal Society of Canada, the agents have been evaluated in extensive studies in a Chemical Institute of Canada and the Canadian rat model of osteoporosis and have been shown to Society of Pharmaceutical Sciences (CSPS), Prix dramatically enhance bone growth when dosed once Galien, “Heroes of Chemistry” Award (American weekly. Such agents have potential for reversing the Chemical Society), Genome BC Leadership Award dangerous and debilitating bone loss encountered in and Health Research Institute Medal of Honour. bone conditions such as osteoporosis that afflict President of the CSPS (2012-2013). millions of people around the world.

Robert Young Selected Abstract for Oral Presentation Robert Young earned a B.Sc. from the University of Victoria (1967) and Ph.D. from the University of A First Report of an Intravesical Therapy with British Columbia (1971). Postdoctoral studies Activity in a Muscle Invasive Bladder Cancer (1971-76) at Imperial College (London), University Xenograft Model (Abstract # 83) of Adelaide (Australia) and at UBC (Vancouver). Research Associate at the Institut de Chimie des Clement Mugabe, CDRD

50s | CSPS/CC-CRS Conference 2016, Vancouver, BC, Canada

Thursday, June 2 SESSION 8: Health Sustainability Evidence

Chair: Mark Harrison, UBC

Role of Patient Reported Outcome Measures Patient Reported Outcome Measures (PROMs) (PROMs) in the Ongoing Evaluation of and Patient Decision Making Treatment and Reimbursement Mark Harrison, Assistant Professor, Faculty of Stirling Bryan, Professor, School of Population & Pharmaceutical Sciences, University of British Public Health, and Director, Centre for Clinical Columbia Epidemiology & Evaluation (C2E2), UBC This talk will discuss opportunities to improve A major driver of cost growth in health care is the decision making at the patient/physician level by rapid increase in the utilization of existing providing evidence from routinely collected technology and not simply the adoption of new PROMs. There is increasing focus on unnecessary, technology. Health economists and their HTA unwanted and inappropriate treatment resulting in colleagues have become obsessed by technology waster in the delivery of health care. Examples will adoption questions and have largely ignored be discussed which highlight how PROMs could ‘technology management’ questions. Technology contribute to a more efficient health care system by management would include the life-cycle assessment supporting patient decisions and providing feedback of technologies in use, to assess their real-world on the expected outcomes and variability in performance, making use of routinely collected data outcomes to inform clinical practice and decision on patient-reported outcomes (PROMs). Such a making. change in focus would allow health economists and health technology assessment analysts to make a Mark Harrison more significant contribution to system efficiency Dr. Mark Harrison is Assistant Professor at the through rebalancing their efforts away from Faculty of Pharmaceutical Sciences, University of technology adoption questions towards technology British Columbia (UBC), where he leads the management issues. Initiative for Sustainable Health Care, and Scientist at the Centre for Health Evaluation and Outcomes Stirling Bryan Sciences (CHEOS) at St. Paul’s Hospital, Dr. Stirling Bryan is an economist with a career-long Vancouver. Dr. Harrison is a health economist and specialization in health care. His early career was epidemiologist whose methodological and research spent in the UK, with appointments in London and interests lie in policy evaluation, patient and Birmingham. In 2005 he was awarded a physician decision making and preferences for Commonwealth Fund Harkness Fellowship and healthcare interventions, and the measurement and spent a year at Stanford University, and then moved valuation of health. Dr. Harrison is applying to Canada in 2008. He is a Professor in UBC’s advances in research, education, and practice in School of Population & Public Health, and Director these areas to the economic principles of health care of VCH’s Centre for Clinical Epidemiology & sustainability. He has been awarded the AFPC New Evaluation. His research seeks to inform policy and Investigator Research Award for 2016. practice. For example, in the UK he had an extensive Dr. Harrison has a long-standing interest in the involvement with the National Institute for Health & study of chronic disease. He is currently involved in Care Excellence (NICE), and in Canada he chairs projects investigating perspectives of health care CADTH’s Health Technology Expert Review Panel, providers, patients and at-risk people on preventative advising on coverage recommendations for devices, treatments for rheumatoid arthritis, policy procedures and programs. evaluations of pharmacist medication reviews and

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accelerated integrated primary and community care intervention and discusses the role of PROMs in this programs for people with chronic diseases. His context. policy work uses the rich administrative data sources available in British Columbia and builds on his track Mohsen Sadatsafavi record in evaluating policy interventions in the UK. Dr. Sadatsafavi is an academic health economist and Before moving to UBC, he worked at the University outcomes researchers in Faulty of Medicine, of Manchester (UK) on a range of projects, University of British Columbia (UBC). He has a MD including evaluating the impact of a national pay for degree, a MHSc degree in epidemiology, and a PhD performance schemes to improve the quality of in outcomes research. Mohsen is the leader of the primary care for chronic diseases, the use of patient- health economics platform of CRRN. The vision of reported outcome measures to evaluate surgical his program of research is improving patient outcomes, and strategies to improve the outcomes and efficiency of health care delivery in communication of risk and uncertainty in physician- Canada through enabling evidence-informed patient interactions. decision making at all levels of care. Dr. Harrison has a first-class Honors degree in Business and Management Sciences (University of Bradford, 2000), and an MSc (University of Patient Reported Outcome Measures (PROMs): Edinburgh, 2002) and PhD (University of Do you Measure all that I Experience? Manchester, 2008) in Epidemiology. He began his research career with the Arthritis Research UK Cheryl L. Koehn, Founder and President, Arthritis Epidemiology Unit in 2002, and then following the Consumer Experts completion of his PhD, at the Manchester Centre for Health Economics, both at the University of Based on a 2016 Cochrane Collaboration meta- Manchester. He also served as an adviser for the analysis, patient reported outcome measures National Institute of Health Research (NIHR) (PROMs) in RA studies over the past 15 years Research Design Service for North West England. reflect the existing RA Core Set measures. Yet, a Dr. Harrison has a strong publication record with 42 number of outcomes from other health domains of publications, 22 as lead author. concern to patients are rarely reported, thus evidence is lacking on their effect at the individual and society levels. These include fatigue, psychological status, PROMs in Action: Changing Outpatient Asthma productivity losses, sleep disturbance, coping, Care by Individualised Approach to Medication among others. Adherence This talk will focus on the challenge and opportunities of broadening the core set of RA Mohsen Sadatsafavi, Academic Health Economist PROMs from the patient perspective. and Outcomes Researcher, Faulty of Medicine, UBC Cheryl Koehn Despite the availability of very effective Ms. Koehn is a person living with rheumatoid medications, the reality of asthma care is highlighted arthritis. Diagnosed 27 years ago, she broke new by poor outcomes mainly due to low adherence to ground by creating the first grassroots arthritis medications. There are many different reasons for organization focusing on the basics of patient rights: low adherence, ranging from lack of belief in education and advocacy. She founded and remains efficacy to barriers to access to side effects of the president of Arthritis Consumer Experts and treatments. It is therefore unlikely for a 'one-size- JointHealth™ family of programs, the first of their fits-all' approach to improving adherence to be kind in Canada, and co-authored Rheumatoid effective. Individualized approaches based on each Arthritis: Plan to Win, published by Oxford patient's needs and values need to be implemented, University Press in 2002. She conceived of and led requiring a close connection between patient and the development of the first robust iTunes arthritis apps. care provider. This presentation highlights the As a volunteer leader, her remarks from the floor design of a clinical trial which is under way in during the Arthritis 2000 conference have been British Columbia that tests the feasibility, efficacy, widely recognized as the catalyst for the creation of and effectiveness of a novel, patient-centred, the federal research-based Canadian Arthritis pharmacist-based adherence improvement Network. Ms. Koehn has been a standard bearer and

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role model for the inclusion of patients in all Selected Abstract for Oral Presentation important discussions and decisions related to arthritis for the past 25 years and today stands as the How is Uncertainty in Risks and Benefits longest serving leader in the arthritis community. Presented in Patient Decision Support Most recently, she was selected a YWCA Women of Interventions? (Abstract # 64) Distinction 2016 nominee in the field of Health and Wellness. Madelaine Bell, UBC

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Thursday, June 2 SESSION 9: JOINT Session with AFPC

Chair: Simon Albon, UBC

complement patient care experience through active Integrating Pharmaceutical Sciences into a learning and pedagogies of engagement. A third key Pharm D Curriculum element of the new curriculum focuses on advanced inquiry, including innovation, complex problem- Scott Singleton, Associate Professor, UNC solving, and scholarship. We will describe our Eshelman School of Pharmacy, University of North systems approach to curriculum transformation at Carolina at Chapel Hill the school, highlight the proposed new curriculum and share early examples and lessons learned. The UNC Eshelman School of Pharmacy is transforming its doctor of pharmacy program in Scott Singleton response to changing societal and workforce needs Scott Singleton is an associate professor and vice as well as increasing global demand for non- chair of the Division of Chemical Biology and cognitive, meta-cognitive and learning-related Medicinal Chemistry in the UNC Eshelman School cognitive skills development in pharmacy education. of Pharmacy at the University of North Carolina at The linear curriculum based on classroom lecture is Chapel Hill. He fosters a school-wide culture of relatively ineffective and long outdated in a digital educational innovation and excellence by leading the world where content is readily accessible. To Academy for Pharmacy Teaching and Learning cultivate the necessary behaviors, skills, attitudes Excellence. He also co-leads his school’s and habits of mind, students must learn by doing Curriculum Transformation Steering Committee that through direct patient care and service learning, is working to transform how professional leadership opportunities, and hypothesis-driven pharmacists are educated. Scott is an award-winning research or quality improvement-driven inquiry. Our teacher of organic chemistry, biochemistry, and school’s new curriculum launched in August, 2015. medicinal chemistry, and co-founded Synereca The new 4-year PharmD program emphasizes Pharmaceuticals. He holds a BA in chemistry and experiential learning throughout: students spend 6 biology from Trinity University in San Antonio, months in pharmacy practice experiences prior to the Texas, and a PhD in organic chemistry from the 4th year, which is fully experiential. The didactic California Institute of Technology. elements of the curriculum were completely redesigned to emphasize learning outcomes that

54s | CSPS/CC-CRS Conference 2016, Vancouver, BC, Canada

Friday, June 3 Breakfast Lecture SPONSORED BY: AGILENT

Chair: Marcus Kim, Agilent

quantitative metabolomic analysis. I will use of Quantitative Mass-Spectrometry Metabolomics these approaches across species to better understand for Direct Biochemical Phenotyping the regulation of central metabolism in model systems ranging from microbes to mammalian Adam Rosebrock, Assistant Professor, Donnelly tumors. Centre for Cellular and Biomolecular Research and I will describe how we are using our quantitative Department of Molecular Genetics, University of metabolomics approach to characterize the Toronto biochemical phenotypes resulting from small molecule treatment, and our efforts to use these Comprehensive analysis of intracellular small phenotypes to understand mechanism of action as molecules, or “metabolomics", is emerging as a well as generate predictive “fingerprints” of drug powerful tool for measuring the biochemical state of MoA. cells and tissues. My group is using a combination of mass spectrometry metabolomics, genetics, and Adam Rosebrock big data analytical techniques to build a quantitative Dr. Adam Rosebrock is an assistant professor in the understanding of the biochemical wiring of cells Donnelly Centre for Cellular and Biomolecular across diverse cellular states. In contrast to the static Research and Department of Molecular Genetics at maps of reactions that adorn textbooks and wall- the University of Toronto, Canada. He has had charts, metabolism is a dynamic, regulated process longstanding interest in using “big data” to address that changes across space and time as cells grow, fundamental biological challenges. The focus of his divide, and face diverse environmental conditions. I research is on understanding the regulation of gene will discuss how my lab is leveraging patterns of expression and biochemical activities that underlie metabolic response to identify and understand cell division, growth, and survival across diverse regulation of pathways and how we are linking external states. The Rosebrock lab actively develops changes in biochemical phenotype back to genotype. new experimental and analytical methods and builds Direct measurement of biochemical state genetic, hardware, and computational tools to enable provides a view that is orthogonal to genomic and high-throughput and high-content biology, with proteomic tools. I will describe several of the particular emphasis on quantitative flow cytometry analytical and software tools my lab has developed and mass-spectrometry metabolomics. to overcome the challenges posed by the chemical diversity of metabolism, and our methods for

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Friday, June 3 SESSION 10: Analytical Innovation to Support Precision Medicine and Biologicals Development

Co-Chairs: Christoph Borchers, University of Victoria, and David Kwok, BRI Bioipharmaceutical Research Inc.

Dhanashri Bagal Distinguishing Leucine and Isoleucine Residues Dhanashri Bagal is currently a Scientist in the in De novo sequencing of mAbs using Nano Discovery Attribute Sciences group at Amgen n LCMS : A Potential to Replace Edman located in South San Francisco. Dhanashri received Degradation her M.S. degree in Chemistry at the University of Georgia in 2006 and joined Amgen in that same Dhanashri Bagal, Eddie Kast, and Ping Cao, year. Currently at Amgen she focusses on protein Discovery Attribute Sciences, Amgen Inc., South characterization and supports proteomics research San Francisco, California 94080, United States programs to understand disease pathways and to identify and validate therapeutic targets. She is also Monoclonal Antibodies (mAbs) are large involved in native mass spectrometry efforts for the heterogeneous molecules that not only make characterization of non-covalent complexes and exceptional therapeutic candidates, but also make intact protein assemblies especially membrane attractive tools for research and diagnostic proteins. applications. De novo sequencing of mAbs, though challenging, becomes necessary when the original cell line or the cDNA is unavailable. An important ImmunoMALDI MS as a Diagnostic Tool for feature in sequencing of mAbs is the discrimination Primary Aldosteronism of isobaric residues (Xle); Leucine (Leu) and Isoleucine (Ile). An incorrect identification of Xle Michael Chen MD MSc, McGill University, site especially in the complementarity determining Department of Diagnostic Medicine, Jewish General regions (CDR) can severely affect the mAb efficacy. Hospital, Montreal, Quebec Even though mass spectrometry (MS) plays a crucial role in sequencing of mAbs, distinction between Introduction: Primary aldosteronism is by far the Ile/Leu residues still remains challenging by MS most common form of secondary hypertension alone. Multistage fragmentation (MSn) in the mass accounting for approximately 10% of all spectrometer can provide enough evidence for hypertensive patients. Screening with plasma renin Ile/Leu discrimination. However, all methods level is crucial, as early diagnosis is associated with reported thus far utilize direct infusion, demanding cardiovascular risk reduction and better patient peptide enrichment which can be labor-intensive. outcome. This study compares a novel iMALDI Here we report an online nanoLC-MS method, plasma renin activity (PRA) assay against two utilizing bottom up mass spectrometry and clinical methods using patient samples. multistage fragmentation, which depending on the Methods: 140 patient samples were collected for nature of the peptide exploits either generation of a comparison on four different instruments. PRA were 69Da ion from Ile or formation of unique w-ions determined using Diagnostics Biochem Canada employing ETD-HCD to discriminate between Leu (DBC) ELISA, iMALDI, and LC-MS/MS (AB and Ile. This sensitive, rapid and reliable method can Sciex). PRA determination by iMALDI was done by easily be incorporated in the de novo sequencing MS two different MALDI-TOF instruments. workflow for accurate determination of Xle Results: Our clinical specimens had PRA results especially for the CDR region. ranging from 0.03 ng/L/s to 5.94 ng/L/s as measured by the DBC ELISA PRA assay, with 45% of patients in the low renin state.

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The iMALDI PRA assay showed excellent unrealized or ignored in the conventional method correlation with two clinical methods. Regression development process, which relies primarily on analyses showed R-squared value ≥ 0.92 and ≥ 0.95, testing the recovery of spiked reference standard. when iMALDI PRA assay was compared to the We present a case study, where a peptide-based ELISA and LC-MS/MS assays, respectively. immuno-affinity capture LC-MS/MS method using Ninety-Six samples were quantitated by iMALDI the target antigen as a capture reagent was developed PRA assay using two MALDI-TOF instruments, to quantify a therapeutic mAb in human serum. yielding an R-squared value ≥0.99. DBC ELISA Surprisingly, even though the same capture reagent PRA assay also revealed excellent correlation when was used, two different capture procedures, stepwise compared to the LC-MS/MS method, with an R- vs. semi-homogeneous, yielded significantly squared value ≥0.92. different results in measuring drug concentrations. Conclusion: Clinical implementation of the high- This phenomenon was unexpected as it was throughput iMALDI PRA assay will still require generally believed that the step of immuno-affinity reference ranges, and cost-effectiveness studies. But capture in LC-MS/MS served primarily for the through optimization of reagents, protocols, robotic analyte enrichment, and the degree of specificity systems, and software, the entire iMALDI platform offered by the capture reagent might not be critical. for PRA determination has been automated into a Further experiments were conducted to investigate robust, and user-friendly diagnostic platform whether biotransformations of the mAb in vivo applicable for use in clinical laboratories. might account for the discrepancy in the measured drug concentrations. Characterization of the mAb Michael Chen dosed in the cynomolgus monkeys and the patients Dr. Michael Chen is a medical biochemist in the revealed three deamidation/isomerization sites in the department of diagnostic medicine at the Jewish CDR regions of the mAb. Evidences indicated that General hospital in Montreal. He received his these biotransformations contributed to the medical degree from McGill University in 2011, differences observed in the behavior of the mAb followed by postgraduate residency in Medical against the capture reagent used in the PK assays. Biochemistry at Jewish General Hospital in This case study demonstrates the importance of Montreal. In 2015, Dr. Chen received his master gaining insights into the in vivo biotransformations degree in Experimental Medicine. His research of antibody therapeutics. Potential impact from interests are focused on clinical method validation biotransformations should be carefully assessed to and translational proteomics. Dr. Chen is currently a ensure the development of an appropriate immuno- member of the Scientific Committee of Mass affinity capture LC-MS/MS clinical PK assay for Spectrometry Applications for Clinical Lab. accurate measurement of recombinant mAb therapeutics

Understanding Biotransformations of a Luna Liu Therapeutic mAb and the Impact on Clinical PK Luna Liu is currently a Principle Scientific Assay Development Researcher in BioAnalytical Sciences (BAS) at Genentech, a member of the Roche group, in South Luna Liu, Jenny Li, Mauricio Maia, Mary Mathieu, San Francisco, California. She received her B.S. Ihsan Nijem, Rebecca Elliott, Surinder Kaur, and degree in Chemistry from Shanxi University, China Keyang Xu, Genentech, Inc., South San Francisco, and her M.S. degree in Analytical Chemistry from CA West Virginia University, Morgantown, West Virginia. Luna has over twenty years of Biotransformations are known to occur to pharmaceutical and biotechnology industry therapeutic monoclonal antibodies (mAbs) in vivo, experience. Since joining Genentech in 2007, she which may lead to changes in certain properties of has been focused on developing and applying mass the molecules. When the modification takes place in spectrometry-based techniques to qualitatively and the CDR regions of the mAb, it may affect its quantitatively study small molecule drugs, binding to the capture or detection reagents (such as monoclonal antibodies (mAbs) and antibody-drug target antigens or anti-ID mAbs) used in its conjugates (ADCs) both in vitro and in vivo. She and pharmacokinetic assay. However, such potential her group have developed and utilized innovative impact by the mAb biotransformations was largely bioanalytical approaches, e.g., affinity capture LC-

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MS to gain novel insights into biotransformations Christoph Borchers and pharmacokinetics of complex biotherapeutics Dr. Borchers received his B.S., M.S. and Ph.D. from such as ADCs in biological fluids/tissues for the University of Konstanz, Germany. After his nonclinical and clinical studies. Such data is proven post-doctoral training and employment as a staff essential for understanding the ultimate fate of scientist at NIEHS/NIH/RTP, in North Carolina, he biotherapeutics in vivo and critical for molecule became the director of the UNC-Duke Proteomics selection and to support regulatory filings. Prior to Facility and held a faculty position at the UNC joining Genentech, Luna worked as a Scientist in Medical School in Chapel Hill, NC (2001-2006). Drug Metabolism and Pharmacokinetics (DMPK) Since then, Dr. Borchers has been employed at the Department at Renovis. She also worked at University of Victoria (UVic), Canada and holds the biotechnology and pharmaceutical companies, current positions of Professor in the Department of including Sugen, Scios, and Oread, where she was Biochemistry and Microbiology and the Don and responsible for LC-MS/MS method development Eleanor Rix BC Leadership Chair in Biomedical and and high-throughput sample analysis to support Environmental Proteomics. He is also the Director efficacy, pharmacokinetics and toxicity studies of of the UVic – Genome BC Proteomics Centre, various programs. which is a member of the Genome Canada funded Genomics Innovation Network. Dr. Borchers is also appointed as Professor at McGill University in the Multiplexed Absolute Protein Quantitation by Department of Oncology, Montreal, QC and LC/MRM-MS for Clinical Research received there the Segal Chair in Molecular Oncology at the Jewish General Hospital of the Christoph H. Borchers, University of Victoria - McGill University. Genome BC Proteomics Centre and Dept. of His research is centered around the Biochemistry and Microbiology, University of improvement, development and application of Victoria, BC Canada proteomics technologies with a major focus on techniques for quantitative targeted proteomics for Mass spectrometry is now poised to make major clinical diagnostics. Multiplexed LC-MRM-MS contributions to personalized method in the area of approaches and the immuno-MALDI (iMALDI) biomarker discovery and validation. Biomarker technique are of particular interest. Another focus of validation -- long the "bottleneck" in the biomarker his research is on technology development and pipeline -- has now become feasible because of application of the combined approach of protein advances made in quantitative proteomics. Large- chemistry and mass spectrometry for structural scale quantitation projects are now possible because proteomics. Dr. Borchers has published over 200 of the development and standardization of highly- peer-reviewed papers in scientific journals and is the multiplexed and accurate quantitative proteomics founder and CSO of two companies, Creative methods, such as multiple reaction monitoring Molecules. Inc. and MRM Proteomics Inc. He is (MRM), for the simultaneous targeting of large also involved in promoting proteomic research and numbers analytes. MRM assays have now been education through his function as HUPO developed for hundreds of proteins for different International Council Member, Past Scientific species in different biological specimen, e.g. blood Director of the BC Proteomics Network and Vice- plasma, urine, CSF, saliva, and DBS. My laboratory President, External of the Canadian National has developed many of these into kits for the use by Proteomics Network. non-experts in mass spectrometry. Recently, we have been working on extending the scope of these MRM-based assays to include mouse proteins, since the mouse is the most commonly used model for human diseases.

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Friday, June 3 SESSION 11: Protein and Peptide Delivery

Co-Chairs: Brian Amsden, Queen's University, and Larry Unsworth, University of Alberta

scaffold materials can be placed in the back of the Selected Abstract for Oral Presentation eye to facilitate long term drug release. However, removal, both at the end of the useful life of the Development of a Segmented Intravaginal Ring device and in the event of complications will be for the Combination Delivery of discussed. In situ gelling materials show significant Hydroxychloroquine and siRNA-encapsulated promise for maintaining therapeutic concentrations Nanoparticles as a Novel Strategy for Preventing over a long time period. Targeted systems which HIV Infection (Abstract #33) use light as well as other methods to facilitate release are also underdevelopment. These methods Yannick Traore, University of Manitoba will lead to a paradigm shift in ocular drug therapy.

The Eyes Have It - Shifting Paradigms in the Heather Sheardown Delivery of Drugs to the Eye Dr. Sheardown (PhD, Chemical Engineering and Biomedical Engineering, University of Toronto, Heather Sheardown, Professor, Department of BEng, Chemical Engineering, McMaster University) Chemical Engineering, Faculty of Engineering. is a professor in the Department of Chemical McMaster University, Hamilton ON Canada Engineering at McMaster University. She joined the Faculty of Engineering at McMaster in 1998, and Traditional methods of delivery of drugs to the eye served as Associate Dean (Graduate Studies) from include eyedrops and more recently injection of 2009-2013. She holds an adjunct appointment at the therapies into the vitreous cavity of the eye. While School of Optometry at the University of Waterloo. the former is well accepted, the inability to target Her research interests are focused primarily on intraocular tissues and significant losses of the active the development of biomaterials and drug delivery agent make this a suboptimal method. As well, eye systems for treating ocular disorders. Her previous drop therapies are limited by patient compliance. studies have included work on the development of Direct injection into the back of the eye, while novel contact lens materials, artificial cornea and effective, has a high incidence of complications and intraocular lens materials and on the development of is therefore only useful for treatment of certain novel methods of delivering drugs to the eye. She advanced conditions. It is clear that there is a real has published over 120 refereed articles, has been an need for better methods of drug delivery. This talk invited speaker at many conferences, and has trained will focus on novel methods of drug delivery to the 10 PhDs. She is the Scientific Director of the 20/20 eye that overcomes some of these issues and the NSERC Ophthalmic Materials Strategic Network challenges faced by each of these methods, including and has led a number of other initiatives related to some discussion of the new materials that are being development of new materials in the eye. She was used to facilitate delivery. Mucoadhesive materials awarded the McMaster University Innovator of the have the potential to increase the residence of drugs Year award and has been recognized as the Hamilton in the precorneal tear film, thereby decreasing the Halton Engineer of the Year. She sits on a number need for frequent drop instillation. However, of grant panels for NSERC and CIHR. She has turnover of the cells of the precorneal epithelium served as a consultant to or worked with a number of remains a limiting factor. Contact lens based drug companies in the field of ophthalmic materials and delivery has shown promise in the lens wearing drug delivery as well as to Health Canada. She has population but may not be appropriate for patients served as associate editor and on the editorial boards who do not currently wear lenses. Insertable of several journals.

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Hollow Metallic Microneedles for Intradermal New Strategies for Protein Delivery from Delivery Degradable Microspheres

Boris Stoeber, Department of Mechanical Brian Amsden, Professor, Department of Chemical Engineering and Department of Electrical and Engineering at Queen’s University Computer Engineering, The University of British Columbia, Vancouver, Canada Proteins are an important drug class because of their potential to treat a wide range of conditions. Microneedles are biomedical microdevices that Compared to small drug entities, protein therapeutics provide a pathway across the skin barrier to are highly specific in their action, and are expected exchange fluids or compounds with the body for to be less toxic than synthetically derived molecules drug delivery or biosensing. This talk will give a as well as to behave more predictably in vivo. They brief introduction into this field. The effectiveness of thus represent a significant potential market. microneedles for intradermal drug delivery has been Because of the stability requirements of proteins and demonstrated in clinical trials, and it has been shown the barriers to their absorption by other conventional that there are several applications that benefit from routes such as oral, nasal, buccal, and transdermal, delivery into the skin compared to intramuscular the route of administration for many therapeutic delivery. In addition, it has been shown that proteins is currently parenteral. However, parenteral intradermal drug delivery using hollow microneedles delivery may not be suitable for a number of protein can be painless. Different types of microneedles drugs. Most therapeutic proteins have a short in vivo have been developed for different delivery half-life and, upon injection, are unevenly strategies. This talk highlights some of the research distributed in the interstitial fluid and unable to reach results on microneedles achieved at the University of the desired physiologic sites. They may also bind British Columbia. unselectively to cellular receptors and thus cause undesirable side effects. Furthermore, many Boris Stoeber therapeutic proteins are produced locally to act on Boris Stoeber received the electrical engineering cells in the immediate environment and are required Diploma from the Technische Universität at the local tissue site for a prolonged period of time. Darmstadt, Darmstadt, Germany, in 1998, the Thus, administration regimens typically consist of general engineering Diploma from the École multiple injections, often at supraphysiologic Centrale de Lyon, Ecully, France, in 1998, and the concentrations, which presents potential problems Ph.D. degree in mechanical engineering from the with patient compliance and possible complications University of California, Berkeley, in 2002. From when administered in a non-clinical setting. A long- 2003 to 2005, he was a Postdoctoral Scientist in term continuous and localized protein drug delivery chemical engineering at the University of California, depot could therefore provide numerous and distinct Berkeley. Since 2005, he has been with the advantages. In this talk I will discuss the potential of Department of Mechanical Engineering and the utilizing low melting point biodegradable polymers Department of Electrical and Computer Engineering to fulfill the requirements of an effective therapeutic at the University of British Columbia, Vancouver, protein formulation for long-term delivery. BC, Canada, where he is an Associate Professor. He holds the Canada Research Chair for Microfluidics Brian Amsden and Sensing Technology, and he is an Associate Brian Amsden obtained his PhD in Chemical Editor for the IEEE Sensors Journal. His research Engineering in 1996, in the area of therapeutic interests include microflow control strategies, flow protein delivery from hydrogels and polymer physics of complex microflows, microflow imaging microspheres. Following his PhD, he worked for methods, microoptical devices, sensing technology, Angiotech Pharmaceuticals in Vancouver as a biomedical microdevices, and fabrication techniques Research Associate, leading projects involving the for microelectromechanical structures. Technology formulation of paclitaxel for localized delivery. He developed through his research is being left Angiotech to join the Faculty of Pharmacy at the commercialized by several start-up companies in University of Alberta in 1997, and is currently a California and in British Columbia. Professor in the Department of Chemical Engineering at Queen’s University where he has been since July 2000. His current research interests

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include the development of biodegradable protein/peptide drug delivery for the treatment of elastomers, hydrogels, and low viscosity diabetes and diseases in the brain. hydrophobic polymers for the local delivery of small molecules, peptides and proteins, and stem cells, and Xiao Yu (Shirley) Wu as scaffolds for soft and connective tissue Dr. Xiao Yu (Shirley) Wu is a full Professor and regeneration. He is the Director of CREATE elected Fellow of American Association of Connect Soft Connective Tissue Regeneration Pharmaceutical Scientists (AAPS). She was trained Network and a principal investigator in the in polymer science and engineering and earned her CREATE Biointerfaces Network. He has received PhD degree in Chemical Engineering with a thesis the Alberta Health Foundation for Medical Research on polyelectrolytes and stimulus-responsive Independent Establishment Award, the Ontario nanohydrogels. After over two-year postdoctoral Premier’s Research Excellence Award, the Queen’s research in pharmaceutics and drug delivery, she University Chancellor’s Research Award, the joined the Faculty of Pharmacy at the University of Ontario Centres of Excellence Award of Excellence Toronto in 1994 as a tenure-track faculty member for Research Collaboration and Commercialization, and promoted to Full Professor in 2006. During her and has been named Fellow Biomaterials Scientists 22 year academic career, Dr. Wu has directed a well- and Engineers. funded innovative research program and become an internationally recognized expert and leader in controlled release dosage forms and novel drug Bioinspired and Nanotechnology-Enabled delivery systems and delivery strategies. She is also Protein/Peptide Drug Delivery for Diabetes and a dedicated educator who has played a leading role Diseases in the Brain in teaching pharmaceutics and drug delivery in the faculty at both graduate and undergraduate levels in Xiao Yu (Shirley) Wu, PhD, FAAPS, Director of past two decades. She has provided excellent Advanced Pharmaceutics & Drug Delivery multidisciplinary training in pharmaceutics, drug Laboratory, Leslie Dan Faculty of Faculty of delivery and drug development to ~140 graduate Pharmacy, University of Toronto, Ontario students, undergraduate research students, and postdoctoral researchers working in her laboratory. Proteins/peptide drugs have been used for treatment She has extensive collaborations with scientists in of various diseases, such as diabetes and cancer, and academia and pharmaceutical industry. Dr. Wu has gained increasing interests as modern therapies. published >380 journal papers, book chapters, However, delivering biologic agents to the intended conference proceedings and abstracts and has targets at effective levels on demand faces delivered >100 invited presentations. She is a co- tremendous challenges. Protein/peptide drugs inventor of 25 issued or pending patents worldwide. usually have very short life-time, are prone to Her current research projects include the design and denaturation and enzymatic degradation, and unable in vitro/in vivo evaluation of blood-brain barrier- to cross the blood-brain barrier (BBB). Dr. Wu’s penetrating nanoparticles for therapy and imaging of Advanced Pharmaceutics and Drug Laboratory has brain cancer and CNS diseases, synergistic drug developed nanotechnology-based delivery systems combination nanomedicine for treatment of that mimic biological systems in the regulation of multidrug resistant and metastatic breast cancer, hormone release or transport of large molecules to hybrid bioreactive nanoparticles for remodeling the brain. In this presentation, Dr. Wu will use two tumor microenvironment and improving tumor examples of bioinspired and nanotechnology- therapy, intelligent polymer and nanotechnology- enabled delivery systems designed in her laboratory, enabled closed-loop insulin delivery implant, and i.e., a glucose-responsive closed-loop insulin computer-aided design of controlled release drug delivery implant and a BBB-crossing nanoparticle delivery systems. system, to discuss how to mitigate the problems of

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Poster Session 1

CSPS and CC-CRS Posters

AFPC Posters

Wednesday, June 1

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Poster Session 1

Wednesday, June 1

MCL-1, survivin, cleaved caspase 3, and cleaved Biomedical Sciences PARP, but gave rise to the expression of p-Stat3 and c-Myc. RU cells converted to RR cells under hypoxia. Unexpectedly, knockdown of HIF-1α under hypoxia increased RU to RR conversion. 1. Can HIF-1α Silencing Overcome Hypoxia Conclusion: Hypoxic condition led to the over- Induced Conversion of Triple Negative expression of HIF-1α, generation of more Breast Cancer to More Tumorigenic and tumorigenic and resistant phenotype in MDA-MB- Drug Resistant Phenotype? 231 cells. Unexpectedly, HIF-1α knockdown under hypoxia resulted in increased conversion of cells to Hoda Soleymani Abyaneh, Nidhi Gupta, Raymond more tumorigenic and resistant phenotype. This may Lai, Afsaneh Lavasanifar. be attributed to the compensating effect of other Faculty of Pharmacy and Pharmaceutical Sciences, transcription factors overexpressed following HIF1- Faculty of Medicine and Dentistry, University of α knockdown under hypoxia. Alberta, Edmonton, Canada

Purpose: The long-term objective of this study is to 2. Replacement of Threonine with Alanine at assess the role of hypoxia inducible factor alpha 1 Position 94 Amino Acid (T94A) of Rat Liver (HIF-1α) as a therapeutic target in triple negative Fatty Acid Binding Protein by Site-Directed breast cancer. For this purpose, we have first Mutagenesis investigated the effect of hypoxia on the conversion of MDA-MB-231 cells to more tumorigenic and Tyson Le, Yuewen Gong, Neal M. Davies and Frank resistant phenotype. The effect of HIF-1α J. Burczynski. knockdown by small interfering RNA (siRNA) on College of Pharmacy, Faculty of Health Sciences, this phenomenon was then investigated. University of Manitoba, Winnipeg, MB, Canada Methods: Parental MDA-MB-231 and its two subsets sorted based on responsiveness to a Sox2 Purpose: Liver fatty acid binding protein (L-FABP) regulatory region (SRR2) reporter were used. The is a cytoplasmic polypeptide that binds long-chain cell subset responsive to SRR2 reporter (RR cells) is fatty acids, eicosanoids, bile acids, and hypolidemic found to be significantly more tumorigenic than the drugs. The L-FABP T94A is a prevalent and reporter unresponsive (RU) cells. Lipofectamine common polymorphic variant. The variant is a complexed HIF-1α siRNA was incubated with cells single-nucleotide polymorphism that has a threonine th and the expression of HIF-1α and its downstream in the 94 position being replaced by alanine. The proteins under hypoxia were analyzed by purpose of this study is to mutate and isolate the immunoblotting. Conversion of RU to RR cells recombinant rat L-FABP to the T94A variant. under hypoxia was investigated by measuring the Further biological studies will be conducted on the level of GFP expression using Flow Cytometric isolated variant to elucidate its biological properties. analysis and luciferase assay. Lastly, the effect of Methods: E. coli from a previous study conducted HIF-1α knockdown on the conversion of RU to RR by our group was confirmed to contain recombinant cells under hypoxic condition was assessed. pGEX-6p-2/L-FABP by purifying the plasmid DNA Results: Higher HIF-1α, p-Stat3, BAK and survivin and digesting with restriction enzymes BamH1 and expression were measured under hypoxia compared Xho1. Site-directed mutagenesis was used to induce th to normoxia in parental MDA-MB-231 cells and its a DNA substitution at the 94 position exchanging two subsets. Successful knockdown of HIF-1α under the threonine for an alanine. DNA sequencing was hypoxia did not produce any significant effect on the conducted to confirm the presence and location of expression of its down-stream proteins, e.g., BAK, the substitution. Recombinant L-FABP T94A was

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expressed and purified in E. coli using a GST tag PPARagonism. system. SDS-PAGE and western blot were Methods: To confirm in silico results, we purchased conducted to detect the recombinant L-FABP T94A a commercially available PPAR competitive variant. binding assay kit and a Cignal Reporter assay kit to Results: Gel electrophoresis confirmed that the E. assess Ibrutinib’s and Dabrafenib’s binding affinity coli contained the recombinant pGEX-6p-2/L- and transactivation potential of PPAR, respectively, FABP. Digestion with restriction enzymes BamH1 using rosiglitazone as positive control. The HepG2 and Xho1 showed two bands, 4900bp was the cell line, which expresses adequate endogenous pGEX-6p-2 and 418bp was the L-FABP. After site- PPAR, was used for assessment of transactivation directed mutagenesis, plasmids were transformed potential. To assess the antifibrotic effects in vitro, into competent DH5α cells, which were then grown we determined the expression of fibrosis biomarkers on agar plates. The results indicate that the mutant and PPAR using qPCR in both quiescent and plasmid was properly transformed. DNA sequencing activated human hepatic stellate cells (LX-2) treated of original and mutated rat L-FABP showed the th with Ibrutinib and Dabrafenib at various substitution of the threonine position 94 was concentrations. substituted for an alanine in the mutated DNA. SDS- Results: The binding EC50 values of Ibrutinib and PAGE and western blot confirmed proper Dabrafenib exceeded solubility limits and 100 μM, purification of L-FABP and L-FABP T94A variant. respectively. Ibrutinib caused limited transactivation Conclusion: Replacement of threonine with alanine of PPAR while Dabrafenib failed to transactivate at the 94th amino acid (T94A) of rat L-FABP was PPAR in HepG2 cells. Ibrutinib and Dabrafenib properly constructed. Original and site-directed decreased the mRNA expression of fibrosis mutant rat L-FABP was successfully purified. biomarkers in activated LX-2 cells, but not PPAR.

Conclusion: Based on our study, Ibrutinib and 3. Tyrosine Kinase Inhibitors Decrease Dabrafenib are poor agonists of PPAR. Reductions Molecular Biomarkers of Fibrosis in in fibrotic biomarkers suggest possible antifibrotic Activated Hepatic Stellate Cells in vitro effects which do not involve the PPAR pathway.

Xiaolei Yang, Meena Sarkharkar and Jane Alcorn. College of Pharmacy and Nutrition, University of 4. Zirconium-89 Labeled Gene Delivery Saskatchewan, Saskatoon, SK, Canada Nanoparticles as Theranostic Agents for Melanoma Purpose: Hepatic fibrosis is a worldwide problem Istvan Hajdu1, Deborah Michel1, Mays Al-Dulaymi1, threatening human health due to the risk of 1 1 complications. Hepatic injury stimulates a wound- Waleed Mohammed-Saeid , Kishor Wasan , Humphrey Fonge2, Ildiko Badea1 healing response and continuous injury results in an 1 excessive accumulation of extracellular matrix Drug Discovery and Development Research Group, College of Pharmacy and Nutrition, University of (ECM), hepatic fibrosis and ultimately cirrhosis or 2 other serious hepatocellular diseases. The Tyrosine Saskatchewan; Department of Medical Imaging, Kinase Inhibitors (TKIs) have shown antifibrotic College of Medicine, University of Saskatchewan effects and may represent a new generation of Saskatoon, SK, Canada antifibrotic drugs. In computational analyses we demonstrated for Ibrutinib and Dabrafenib, two Purpose: The overall approach to use targeted recently approved anticancer TKIs, had more nanoparticles as carriers, for both therapeutic and favourable binding energies to PPAR than the contrast agents is that drug delivery and efficacy can be monitored simultaneously in a non-invasive known PPARagonist, Rosiglitazone, which also manner. The goal of our research was to develop a has reported antifibrotic effects in the liver. The specific Zirconium-89 (89Zr) -labeled DNA delivery nuclear receptor, peroxisome proliferator-associated nanosystem and clarify its in vitro and in vivo receptor--, is involved in cell proliferation and behavior. ECM production. Based on the above observations, Methods: DNA containing nanoparticles were we hypothesize that Ibrutinib and Dabrafenib formulated using peptide-modified gemini lipid and suppress hepatic stellate cell activation via deferoxamine modified gemini lipid. The

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nanoparticles were characterized by dynamic light health. Although resveratrol is well-tolerated in scattering, zeta potential analyzer and wide-angle X- humans, it is readily metabolized and exhibits low ray scattering and radiolabeled with 89Zr. bioavailability. Therefore, we queried whether Radiolabeling efficiency, serum stability, gene resveratrol analogues would produce greater expression and cell viability were investigated in vasculoprotective effects in an experimental model A375 human melanoma cells. Biodistribution and of hypertension and heart failure. pharmacokinetic profile were examined in athymic Method: Sprague-Dawley (SD) and SHHF rats CD-1 nude mice by gamma counter. (n=8) were treated for 8 weeks by gavage with Results: The average hydrodynamic size of the vehicle control (C) or low doses (2.5 mg/kg/d) of nanoparticles was 114±2 nm and zeta potential resveratrol (R), pterostilbene (P), and gnetol (G). +31.6.3±1.4 mV. A high labeling stability of the Blood pressure was measured by tail-cuff 89Zr-labeled nanoparticles was observed, and gene plethysmography. Animals were anesthetized and expression was similar to the non-labeled third-order mesenteric resistance arteries were formulations. The nanoparticles showed longer isolated. Vascular function, structure and mechanical plasma half-life (t1/2 = 10.1 ± 0.4 h vs. t1/2 = 1.3 ± 0.1 properties were evaluated by pressure myography. h) compared to the lipid alone. As expected, the Results: Systolic blood pressure was increased in 89Zr-labeled nanoparticles showed higher liver the SHHF rat (1963 mm Hg, vs. SD 1427 mm Hg, accumulation (33.87 ± 2.20% ID/g vs 20.75 ± 5.35% p<0.01), and was unaffected by stilbenoid treatment. ID/g,) and lower kidney accumulation (0.96 ± 0.08% Lumen diameters were reduced in SHHF vessels ID/g vs 1.34 ± 0.16% ID/g) of the compared to (2005 m vs. SD 3189 m, p<0.01). As media radiolabeled lipid, which suggests that the cross-sectional area was unchanged, media-to-lumen nanoparticles remained intact in the blood, and these ratios increased (SHHF 17.41.2 vs. SD 8.90.5, intact nanoparticles spend sufficient time in the p<0.01); these changes mimic the “eutrophic blood stream for a specific tissue accumulation. remodelling” that occurs in resistance arteries from Conclusions: The DNA containing radiolabeled patients with essential hypertension. Lumen delivery system was successfully prepared. The narrowing in SHHF arteries was attenuated by labeled nanoparticles were stable and showed similar resveratrol and pterostilbene (SHHF-R 2376 m in vitro characteristics to the non-labeled and SHHF-P 2386 m, p<0.01), but not gnetol nanoparticles. It was established that the intact (SHHF-G 2239 m), whereas media-to-lumen ratio nanoparticles have significantly different was reduced toward normal by all three stilbenoids pharmacokinetic and accumulation profile compared (SHHF-R 13.80.8, SHHF-P 13.70.5, SHHF-G to the lipid and show potential for applications in 13.00.3, p<0.01). targeted cancer gene therapy. Conclusion: The mesenteric resistance arteries of

the SHHF rat exhibit eutrophic remodeling, 5. Disparate Effects of Resveratrol and modeling small artery disease in human essential Analogues (Pterostilbene and Gnetol) in the hypertension. Resveratrol, pterostilbene, and gnetol Spontaneously Hypertensive Heart Failure failed to lower blood pressure; importantly, this (SHHF) Rat suggests that vascular improvement was not secondary to blood pressure lowering, but rather a Danielle I. Lee,1,2 Crystal Acosta,2,3 Bolanle C. result of direct actions on the arterial wall. Thus, Akinwumi,1,2 Zongjun Shao,2 and Hope D. further research on stilbenoid polyphenols as an Anderson.1,2,3 adjunct to current anti-hypertensive therapy is 1College of Pharmacy, University of Manitoba; warranted. 2Canadian Centre for Agri-food Research in Health and Medicine, St. Boniface Research Centre; 3Department of Pharmacology and Therapeutics, University of Manitoba; Winnipeg, Canada

Purpose: Significant research interest to date has focused on the polyphenol, resveratrol (trans-3,5,4’- trihydroxystilbene), a stilbenoid that is purportedly linked to improved longevity and cardiovascular

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6. Characterization of Low Affinity Folate 7. Demystifying Molecular and Cellular Transporters at the Blood-Brain-Barrier Mechanisms for Identifying Druggable Targets within Breast Cancer Cell Lines Marc Li, Camille Alam1, Reina Bendayan1 Using Newer Tyrosine Kinase Inhibitors 1Department of Pharmaceutical Sciences, University of Toronto, Ontario, Canada Franklyn De Silva, Karun Sharma, Meena Sakharkar, and Jane Alcorn. Purpose: Folates (vitamin B9) play an important Drug Discovery & Development Research Group, role in tissue development and repair. Three major College of Pharmacy and Nutrition, University of transport systems exist by which folates enter cells: Saskatchewan, Health Sciences Building, Saskatoon, the proton-coupled folate transporter (PCFT), Saskatchewan, Canada reduced folate carrier (RFC), and folate receptor alpha (FRα). Of these transporters, FRα binds to Purpose: The human epidermal growth factor folates with the highest affinity (KM = 1nM) and receptor (HER), the estrogen receptor (ER), and plays a predominant role in brain folate uptake at the progesterone receptor (PR) expression, choroid plexus. Mutations to and/or antibodies amplification, and the absence of these receptors against FRα can cause severe folate deficiency in the play a major role in tumor survival. Tyrosine kinases brain and result in early childhood (TKs) govern cancer progression and control. neurodegeneration. We hypothesise that in the Several small molecule inhibitors of TKs (TKIs) context of mutations and/or presence of FRα (targeted therapy) have been successfully used antibodies that would impair folate uptake at the clinically. Ibrutinib (ImbruvicaTM), an orally choroid plexus, the low affinity folate transporters administered, irreversible inhibitor marketed as a (PCFT and RFC) expressed at the blood-brain Bruton’s Tyrosine Kinase (BTK) inhibitor for barrier (BBB) could play a significant role in brain treatment of several B-cell malignancies, has folate uptake. The aim of this project is to recently shown greater cytotoxicity towards HER2 characterize the function of the low affinity folate positive breast cancer (BC) cells. Interestingly, transporters at the BBB. Ibrutinib is not exclusive to BTK. Therefore, we Methods: Transport assays were conducted in a decided to use Ibrutinib as a model drug to evaluate human brain microvessel endothelial cell line the changes in expression of several protein kinases (hCMEC/D3) representative of the BBB. Uptake of (PKs) in heterogeneous forms of BC cell lines in radiolabelled folic acid (3H-FA) was measured at pH order to find translational evidence to support the 5.5 and 7.4, which reflect the optimal pH of PCFT idea of utilizing Ibrutinib and several other newer and RFC, respectively, as well as in the presence of TKIs as candidates for the treatment of primary and standard PCFT inhibitors (4,4’-diisothiocyano-2,2’- difficult to treat metastatic breast cancer. stilbenedisulfonic acid or DIDS, Methods: We plan to identify key targets within bromosulfophthalein or BSP, and sulfasalazine). HER2 dependent and independent pathways Results: 3H-FA uptake by hCMEC/D3 cells was primarily using various in-vitro assays (cytotoxicity, stimulated by an acidic extracellular pH, with time- mitochondrial activity, and protein and RNA dependent uptake being higher at pH 5.5 compared expression). to 7.4. At pH 5.5, 3H-FA uptake was significantly Results: In a preliminary study by our lab, Ibrutinib inhibited by DIDS (55%), BSP (45%), and caused complete tumor regression in an sulfasalazine (40%). immunocompromised orthotopic murine model Conclusion: The pH dependency and susceptibility using the M4A4-GFP cell line. The relative cellular to PCFT inhibitors suggest a potential role for PCFT cytotoxicity of ibrutinib, evaluated by different in folic acid uptake at the BBB. Further work will assays (primarily: Calcein AM assay) for HER involve full characterization of PCFT kinetic and positive (+) cell lines was <100 nM while 5000 - energetic properties in hCMEC/D3 cells. Further 12,000 nM for ER-PR positive (+), and >15000 nM work will also be conducted to investigate the role of for ER-PR negative (-) cell lines. nuclear receptors in regulating folate transporters, Conclusion: These preliminary results provide particularly PCFT, at the BBB. evidence for Ibrutinib’s interference in HER family Acknowledgement: I am a recipient of the 2016 mediated pathways within HER2 amplified cells and National Summer Student Research Program Award interference with HER members and other PKs in sponsored by GlaxoSmithKline Inc. non-HER2 amplified BC cells.

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8. Characterizing the Molecular Signaling inflammatory proteins/total remains to be Pathways in the Cerebral Arteries of Stroke- determined. prone Spontaneously Hypertensive Rats (SHRsp) Before and After Stroke 9. Effects of a Binge Drinking Ethanol Killol S Chokshi1, Marwan Barakji, Hilary Chang, Administration Protocol on the Long-term Jules Doré2, Noriko Daneshtalab1 Motor Function and Cerebellar Physiology of 1School of Pharmacy, 2School of Biomedical Adolescent Rats Sciences, Memorial University of Newfoundland 1 1,2 Matthew Lamont and John T. Weber 1 2 Introduction: A loss of cerebral blood flow School of Pharmacy and Division of Biomedical autoregulation in stroke-prone spontaneously Sciences, Memorial University of Newfoundland, hypertensive rat (SHRsp) is associated with St. John’s, NL, Canada hemorrhagic stroke. To understand why fatal stroke risk is elevated in patients with inflammatory Purpose: Binge drinking among adolescents is a diseases, we use SHRsp’s middle cerebral arteries growing public health concern. Although binge (MCA) to study the underlying signalling change drinking can also be harmful to adults, the may be occurring before stroke develops, leading to adolescent population is more susceptible to aberrant dysregulation of MCA contraction, which may be neurological changes as their brains are still responsible for the loss of the ability of the MCAs to undergoing significant development. The goal of this autoregulate after stroke. project is to provide firm evidence that there are Methods: MCA samples from SHRsp animals are changes occurring to physiology in the cerebellum, collected at 9 weeks for pre-stroke and after an area of the brain important for motor coordination evidence of stroke (around 15 weeks or more) for and learning, after binge drinking. post-stroke. The MCAs were either isolated to Methods: Rats of two different ages were used in measure protein levels and expression using western order to examine the effects of ethanol on adolescent blot or immunofluorescence. Tissues were analyzed (PND 30) and periadolescent (PND 26) subjects. for activation of neuro-inflammation, total and Behavioral testing consisted of the fixed speed rota- activated inflammatory proteins (ERK and MAPK), rod (FSRR), accelerating rota-rod (ARR), and cage and proteins involved in cerebrovascular contraction hang tests designed to assess motor function. After (PKC an MLC). being divided into equal groups of experimental and Results: Preliminary results from IHC indicate control, subjects were exposed to either ethanol or activated inflammatory proteins (ERK & MAPK) & plain air through a vapour chamber apparatus for neuroinflammatory markers (astrocytes & five consecutive days. Blood ethanol concentrations Microglia) are increased after stroke with an (BECs) were taken on each treatment day after associated decrease in expression of activated exposure in both groups. Behavioral tests were protein kinase C(PKC-involved in activating conducted prior to beginning the ethanol exposure, contractile proteins) compared to pre-stroke SHRsps. on each exposure day before being placed into the Preliminary results from western blot shows vapour chamber, and at several other times for the significantly lower phospho ERK/Total ERK, as month following treatment. well as a significantly lower Phospho MAPK/Total Results: Results from the FSRR and cage hang MAPK in post stroke animals in comparison to pre testing indicated a significant difference between stroke group. Post stroke samples also show groups that persisted for up to 30 days after significantly lower Total MAPK/GAPDH, but treatment. The ARR testing did not show as strong appear to have a significantly higher Total an effect and it only persisted for approximately one ERK/GAPDH compared to pre stroke. Conversely, week after treatment. post stroke MCAs appear to have a numerically Conclusion: Additional studies are currently higher phospho PKC/Total PKC when compared to underway and will utilize a number of techniques in pre stroke. order to investigate the biological changes in the Conclusion: Overall, it appears that there is an cerebellum. These results will allow us to more increase in active inflammation and decrease in conclusively state that binge drinking during active PKC (involved in contraction). The adolescence can cause significant changes to consequence of decrease in the ratio of active cerebellar function at the neuronal level.

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10. Chemical Analysis and Neurobiological neurodegenerative diseases. Effects of Newfoundland Wild Blueberries

Michelle Debnath-Canning1, Scott Unruh1, Poorva 11. Cobalt (III) Complexes as Pro-drugs for Vyas2, Andrei Igamberdiev2 and John Weber1 Cancer Therapy 1School of Pharmacy and 2Department of Biology, Memorial University of Newfoundland Chen Zhang, Mathew Sutherland, Linus Chiang, Ryan Clarke, John Thompson, Charles Walsby and Purpose: In order to treat some neurological Tim Storr. diseases, antioxidants such as polyphenols and Simon Fraser University, Burnaby, BC ascorbate found in Vaccinium berry species may be an effective addition to medicinal products. Purpose: Cancer is one of the leading causes of Polyphenols may reduce oxidative stress and death, and though numerous cancer treatments have inflammation, processes believed to contribute to been developed, the overall selectivity and degenerative disorders such as Parkinson’s disease. effectiveness of treatments need to be improved. We have performed an analysis of the biochemical Exploiting differences between cancerous tissue and attributes and neurobiological activity of compounds normal tissue has proven successful, and compared detected in Vaccinium species. In particular, we are to normal tissue, cancerous tissue exhibits investigating the effects of berry extracts on uncontrolled growth leading to inefficient blood microglia, which are the innate immune cells of the vessel formation, restricting blood flow and the brain. delivery of drugs and oxygen to the inner regions of Methods: Wild blueberries, native to tumors. The lack of oxygen, termed hypoxia, results Newfoundland and Labrador (NL), were collected in a reducing environment in tumors. Exploiting the from different locations. Biochemical assays were reducing environment of tumors to activate a drug performed to determine the phenolic content of molecule offers a potentially selective treatment extracts and antioxidant capacity. Ascorbic acid strategy. We aim to design pro-drugs that are levels in wild lingonberries and blueberries were initially administered to the body in an inactive also determined. To quantify and identify major form, and can be only selectively activated under the anthocyanins in extracts, High-Performance Liquid reducing conditions found in tumors. Chromatography Mass-Spectroscopy (HPLC-MS) Methods: We synthesized octahedral CoIII analysis was performed. Microglial cells isolated complexes in which the metal center is coordinated from mouse brains were treated with glutamate or α- by a tetradentate salen ligand and two axial synuclein to induce inflammatory responses, and fluorescent ligands. The fluorescence is quenched treatment with extracts was conducted in order to while bound to the CoIII center, but upon release we assess neuroprotective effects. can use fluorescence spectroscopy as a proof-of- Results: Biochemical assays indicated that leaves principle for our design strategy. have a significantly higher content of polyphenols and ascorbate in comparison to fruits. Blueberries Results: Upon reduction of the CoIII metal center to had a higher level of ascorbate in both the leaf and CoII, the axial ligands were released from the more fruit extract compared to wild lingonberries. kinetically-labile metal centre, and fluorescence Utilizing HPLC-MS, more anthocyanins were release was observed. Salen ligand modification identified in blueberry fruit than leaves, but the provides a mechanism to tune the reduction potential anthocyanins present in leaf extracts were present in of complexes for selective release in the reducing higher quantity. Cell culture experiments are still environment of tumors. ongoing, to determine the potential of berries to inhibit inflammatory responses in the brain. Conclusion: Wild blueberry fruits and leaves native to NL are high sources of antioxidants, especially phenolic and ascorbate levels. Leaves have an overall significantly higher level of antioxidants compared to the fruits. The results of the cell culture experiments could demonstrate the preventative role that blueberry fruits and leaves have on certain

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Conclusion: This methodology can be utilized for these ligands. CoIII complexes as a drug delivery platform for the selective release of axially-bound anticancer agents. 13. Long-term Adipose Tissue Preservation by Oxygen Delivery 12. Identification of the Mechanism of Action of Chemical Probes Against the Key Autophagy Huaifa Zhang1, Enrico Campioli2, Benjamin Enzyme ATG4B Dalisson1, Vassilios Papadopoulos2, Jake Barralet1,3 1Faculty of Dentistry, McGill University, Montreal, Peter G. K. Clark, Damien Bosc, Lubomir QC; 2Department of Medicine, Faculty of Medicine, Vezenkov, Suzana Kovacic and Robert N. Young. McGill University, 3Division of Orthopaedics, Department of Chemistry, Simon Fraser University, Department of Surgery, Faculty of Medicine, McGill Burnaby, British Columbia, Canada University, Montreal, QC, Canada

Purpose: Autophagy, the catabolic process Purpose: Maintaining adipose tissue viability is responsible for degrading and recycling cellular very important for the study of metabolic activities components, has been implicated in numerous of adipose tissue, fat transplants for reconstruction disease states, including neurological disorders and and obesity. We sought to preserve a large volume many cancers. Although it has been postulated that of adipose tissue under anoxia by encapsulating inhibition of ATG4B, a key enzyme in autophagy, adipose tissue into an oxygen delivery scaffold and may allow modulation of these conditions, no evaluated both cell viability and functionality of the chemical probes have been reported to date with tissue. which to test this hypothesis. Two chemical probes Method: Oxygen releasing ~50-200µm against ATG4B have been developed in our microparticles consisting of calcium peroxide laborotories; however, with the exception of (CaO2) in a polymeric matrix were prepared. For in computational modeling, the binding site for these vitro tissue preservation, the effect of oxygen compounds remains unknown, hindering concentration on cell viability was investigated by identification of their mode of action and further changing the concentration of microparticles in the optimisation. scaffold. Adipose tissue encapsulated in alginate Methods: Enzymatic assays of ATG4B can be used only was used as a negative control. The scaffolds to study the kinetics of inhibition of these were cultured under anoxia for up to 25 d. ELISA compounds, giving evidence towards the mode of was performed to examine necrosis and inhibition. Alternatively, development of photoaffinity probes bearing photolabile groups can (TNF) and lipocalin-2. Finally adipose tissue be used to irreversibly label the binding site, which transplantation was attempted in cylindrical polymer can then be identified using peptide digests and the moulds and the effect of oxygen delivery on tissue known crystal structure of the enzyme. necrosis and resorption was determined. Results: Kinetic evidence has been obtained towards Results: Oxygen supply maintained high cell the binding mode of the qunioline-based chemical viability in adipose tissue under anoxia for up to 25 probe, which has been compared to that predicted days. Viability of spheres of tissue up to 1cm in from in silico modeling. Concomitantly, a derivative diameter could be maintained in anoxia throughout of the thiazole-based probe has been designed and their thickness for up to 7 days. The oxygen synthesised featuring a photolabile diazirine group. preserved adipose tissue secreted a significantly less This photoaffinity probe has a comparable affinity to TNF. the parent compound, suggesting the binding mode Conclusion: Oxygen delivery successfully is unaffected by the introduced group. Labelling prolonged preservation of adipose tissue in vitro. studies and protein digests are ongoing to identify This method could be used to build an ex vivo the localisation of this compound. models of adipose tissue for pharmaceutical and Conclusion: Enzyme kinetics and the development metabolic studies e.g. in the search for a non- of a photoaffinity probe have lent evidence towards surgical approach to morbid obesity treatment. the binding sites of these chemical probes against ATG4B, assisting in both the identification of their mechanism of action and in further optimisation of

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Clinical Sciences & Pharmacy 15. A Comparative Risk of Cardiovascular Events between Incident SSRI and SNRI Use: Practice A Population-based Study

Lindsay Baum1; Silvia Alessi-Severini1; Murray W. Enns2; Jitender Sareen2; James Bolton2; Heather J. 14. Ethnicity and Natural Health Products Prior3; Yao Nie3; Dan Chateau3; Christine Leong1 Usage: Perceptions, Safety, and Pharmacoeconomics 1 College of Pharmacy, Faculty of Health Sciences; 2 College of Medicine, Faculty of Health Sciences; 3 Dalya Abdulla, Sheridan College Institute of Manitoba Centre for Health Policy; College of Technology and Advanced Learning, Brampton, ON Medicine, Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada Purpose: Despite studies looking at immigrant use of NHPs, few have considered economic impacts Purpose: Selective serotonin reuptake inhibitors along with perceptions and attitudes towards such (SSRI) and serotonin norepinephrine reuptake use. The aim of this study was therefore to determine inhibitors (SNRI) are widely prescribed for mood new immigrant patterns of NHP use in order to and anxiety. SNRIs have been associated with guide the provision of complete and comprehensive hypertension; however, the clinical significance of health care to this patient group. SNRIs contributing to cardiovascular events relative Methods: A survey consisting of 40 questions was to SSRIs is unclear. We aimed to compare the risk of completed by new immigrants in the Brampton and cardiovascular events between the incident use of Oakville areas of Ontario during English Language SSRIs and SNRIs. Training classes offered in the years of 2012 and Methods: This was a population-based, 2013. retrospective cohort study of Manitoba residents Results: Almost all participants believed that NHPs using administrative databases from the Manitoba can be used for general health in addition to certain Centre for Health Policy. All patients who started an conditions; when prompted on whether they believed SSRI or SNRI between April 1, 1998 and March 31, NHPs can be considered safe, many participants 2014 were included. The primary outcome was a agreed that NHPs are not safe however were unable composite of myocardial infarction (MI), stroke, or to provide robust examples of unsafe NHP and cardiovascular-related hospitalization within one medication combinations. From a year of drug initiation. Each component of the pharmacoeconomic standpoint, most participants primary outcome was analyzed separately in a indicated that the price of NHPs was within their secondary analysis. Inverse probability of treatment budget while the price of prescription medications weighting with propensity score was used to account was not. Perhaps most interesting were the results for baseline differences between the two groups. related to purchases made by new immigrants for Results: A total of 225,504 and 54,635 patients short and long term illnesses: a high percentage of initiated treatment on an SSRI and SNRI, participants would purchase the prescription respectively. No significant difference was observed medication for a short term illness over the natural for the primary outcome (hazard ratio = 1.01; 95% health product; however this percentage decreases in CI 0.96-1.07), which was experienced by 4467 the event of a long term illness, with more (2.0%) and 897 (1.7%) in the SSRI and SNRI group, participants relying on natural health products to respectively. Secondary analyses also found no remedy their long term illness symptoms. differences in the risk of MI or fatal stroke between Conclusion: The results of this study illustrate that SSRIs and SNRIs. However, the risk of non-fatal many new immigrants utilize NHPs and rely on such stroke was higher among SNRI users (hazard ratio = products for short and long term illnesses. The 1.11; 95% CI 1.04-1.20), and the risk of participants appeared not to be able to identify NHP- cardiovascular-related hospitalization was drug interactions nor appreciate the definition of an unexpectedly lower in the SNRI group compared to adverse event. These results can be used to guide SSRI users (hazard ratio = 0.87; 95% CI, 0.80-0.95, safer clinical practices for new immigrants by respectively). educating health care professionals on common Conclusion: Incident SNRI use was not associated perceptions of such products. with a higher risk of cardiovascular events relative to

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SSRIs. However, further study is warranted for the (parent and conjugates) were significantly elevated higher risk of non-fatal stroke and lower risk of in participants receiving treatment, compared with cardiovascular-related hospitalization observed placebo group (p<0.05). Flaxseed lignan complex among incident SNRI users. administration decreased systolic blood pressure (SBP) to 140±11mmHg vs placebo 154±10 mmHg at 24 weeks in the SBP≥140 mmHg subcategory 16. A Safety Evaluation of Flaxseed Lignan (p=0.04). No significant changes were found in the Supplementation in Healthy Older Adults SBP<140 mmHg subcategory between treatment and Following 6 Months of Once Daily Oral placebo groups. With respect to respiratory rate, Administration pulse, IL-6, TNF-α, and CRP, no significant difference was found between treatment and placebo a b a Yunyun Di , Jennifer Jones , Kerry Mansell , Susan group during the 6-month study. Study participants a c d Whiting , Sharyle Fowler , Lilian Thorpe , Jennifer did not report any significant adverse events a a a Billinsky , Navita Viveky , Pui Chi Cheng , Ahmed associated with flaxseed lignan supplementation. a e a Almousa , Thomas Hadjistavropoulos , Jane Alcorn Conclusion: Our data suggest that long-term aDrug Discovery and Development Research Group, flaxseed lignan complex supplementation was well College of Pharmacy and Nutrition, University of tolerated in healthy, elderly adults. Saskatchewan; bCollege of Medicine, University of Saskatchewan; cDivision of Gastroenterology, College of Medicine, University of Saskatchewan, 17. A Systematic Review and Bayesian Network Canada; dCommunity Health and Epidemiology, Meta Analysis (NMA) to Indirectly Compare College of Medicine, University of Saskatchewan, the Efficacy of the Subsequent Entry Biologic Saskatoon, SK. eRegina Qu’Appelle Health Region, (SEB) CT-P13 to REMICADE® (infliximab) University of Regina, Canada in Patients with Crohn’s Disease (CD)

Purpose: A randomized, double-blind, placebo- George Dranitsaris, PhD, Augmentium Pharma controlled clinical trial was designed to further Consulting Inc. Toronto, Canada; and Brian Feagan, assess the safety and tolerability of a flaxseed lignan MD, Robarts Research Institute, University of complex (~38% secoisolariciresinol diglucoside Western Ontario, London, Ontario, Canada (SDG)) in elderly healthy populations for 6 months following once daily oral administration. This study Background: CT-P13, a SEB (or biosimilar) to was approved through Health Canada REMICADE®, was approved by Health Canada (NCT01846117) and U of S Biomedical Research (HC) using a structural demonstration of similarity Ethics Board and participants were recruited and a reduced package of non-clinical and clinical between 2013 April and 2014 March. data. HC did not grant the CD and ulcerative colitis Methods: 32 participants completed the trial after (UC) indications due to unresolved residual applying all exclusion criteria. Trough blood uncertainty in the absence of clinical data in IBD. In samples were collected at baseline, 8, 16, and 24 the interim, observational studies have reported real weeks to assess plasma inflammatory markers and world experience with use of CT-P13 in IBD. The plasma flaxseed lignan metabolites. Blood pressure, intent of this study was to use Bayesian NMA respiratory rate, pulse, cognition, weight, and height methodology to indirectly compare response and were measured by research staff. Inflammatory remission rates between CT-P13 and REMICADE® markers, IL-6, TNF-α, and C-reactive protein (CRP), in CD using published clinical data. were measured using commercially available kits. Methods: A systematic review of major databases The plasma levels of flaxseed lignan was conducted for placebo controlled randomized secoisolariciresinol (SECO), enterodiol (ED), and trials (RCTs) evaluating REMICADE® in CD. A enterolactone (ENL) were determined using a second review was undertaken to identify all previously validated LC/MS/MS method. published clinical data for CT-P13 in similar Experimental data were analyzed separately using patients. To match the CT-P13 single arm study to one-way ANOVA with repeat measures by SPSS the REMICADE® NMA, a similarity metric was (IBM SPSS Statistics 22, NY, US). The treatment to constructed. The metric is expressed on a scale placebo significance was set at p=0.05. between 0 and 1. CT-P13 study arms with a metric Results: Flaxseed lignan plasma metabolite levels value of ≤ 0.10 were deemed similar enough to be

From Drug Discovery to Health Outcomes: Population to Patient | 71s

® added to the REMICADE NMA. euthanized with CO2 0, 15, 30 and 60 minutes after Results: Three REMICADE® RCTs were dosing and their stomach and small intestine was identified. CT-P13 data in CD included five single surgically removed. After removal the stomach and arm uncontrolled studies, evaluating a mix of CD intestinal content was collected and centrifuged for and UC patients, some having prior exposure to 10 min. The supernatant was discarded and the pellet REMICADE®. The similarity metric indicated that was collected and analyzed by X-ray powder none of the CT-P13 trials were similar enough to be Diffraction (XRPD). incorporated into the REMICADE® NMA. Results: XRPD diffractograms of the stomach and Therefore given the available CT-P13 data, the intestinal content of the rats dosed with LBF without NMA could not generate comparative efficacy danazol, were absent of any crystalline matter. The estimates with any reliability. diffractograms of the stomach content of the rats Conclusions: Despite best efforts, a NMA could not dosed with LBF containing danazol showed be reliably performed to indirectly compare CT-P13 reflections corresponding to those of crystalline to REMICADE®. Consequently, uncertainty with danazol, regardless of dosing time. None of the rats respect to comparative efficacy between CT-P13 and showed evidence of crystalline danazol in the REMICADE® in CD remains. Until data from RCTs intestinal content. becomes available, comparative safety and efficacy Conclusion: The presence of reflections remains undetermined. corresponding to those of danazol in the stomach content of all the rats, regardless of dosing time, indicates that danazol precipitates instantly upon dispersion in the stomach. This was in line with Drug Delivery & Pharmaceutical previous in vitro lipolysis studies of this LBF, suggesting immediate precipitation of danazol upon Technology dispersion1. The absence of crystalline danazol in the intestinal content might be due to no transfer of formulation from stomach to the duodenum, as LBFs have been showed to induce a semi-fed state, 18. In vivo Precipitation of Poorly Soluble Drugs delaying gastric emptying . It could, however, also from Lipid Based Formulations be due to fast absorption of danazol in the

duodenum, thus forcing the equilibrium of danazol Maria Høtoft Michaelsen*1,, Philip Sassene*1, Kishor towards the solubilized state. This study shows that M. Wasan2,, Huiling Mu1, Thomas Rades1 and precipitation of poorly soluble drugs in vivo actually Anette Müllertz1. *These author contributed equally occurs. It is, however, yet to be confirmed if it to the work. affects the bioavailability. 1Department of Pharmacy, Faculty of Health and

Medical Sciences, UCPH, Copenhagen, Denmark; 2 College of Pharmacy and Nutrition, University of 19. Investigation of CD205 Targeted PLGA Saskatchewan, Saskatoon, SK, Canada Nanoparticles to Enhance Antigen Specific Immune responses Purpose: The purpose of this study was to investigate if a poorly soluble model drug danazol Sheikh Tasnim Jahan, Azita Haddadi precipitated in the GI-tract after administration of a Division of Pharmacy, College of Pharmacy and LBF to rats. Nutrition, University of Saskatchewan, Saskatoon, Methods: A LBF consisting of Transcutol HP and SK Kolliphor EL (1:1) was prepared and danazol was added to yield a drug load of 52.4 mg/g (80% of Purpose: Cancer vaccines are designed to work by saturation solubility in the LBF). Male Sprague activating cytotoxic T cells and directing them to Dawley Rats (300-325 g) were fasted for 18 hours recognize and act against specific type of cancer with free access to water and received 250 µL antigen or by inducing the production formulation in a single dose via oral gavage, of antibodies that can recognize cancer cells. The corresponding to approximately 13.1 mg aim of this research is to design a vaccination Danazol/rat. Two rats were administered 250 µl LBF strategy based on nanoparticulate (NP) drug delivery without danazol as a control. The rats were system.

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Method: FDA approved poly-(D, L-lactic-co- and cancer therapy. SRD involves the incorporation glycolide) (PLGA), ovalbumin (OVA, antigen) and of dynamic covalent linkages, which can be later monophosphoryl lipid A (MPLA, adjuvant) is cleaved in response to external stimuli, preferably utilized to prepare NPs by emulsification solvent cellular components. Thus, SRD-exhibiting evaporation method. The dendritic cell targeting nanocarriers, which are stable under physiological ligand (anti-CD205) was attached to NPs via conditions during blood circulation, can be adsorption and covalently binding method. dissociated in a controlled fashion as cellular Results: Formulations had shown suitable components provide the appropriate stimuli to physicochemical properties with 79-93% of cell trigger biodegradation in microenvironments of viability after 72 hours. Structural integrity of OVA tumors and inside cancer cells. Numerous methods in NPs was confirmed through circular dichroism. have been reported for the synthesis of stimuli- COOH and ester terminated PLGA NPs released responsive degradable block copolymers and their 50% OVA in 24 hours and 7 days, respectively. T self-assembled nanostructures. However, most cell proliferation study confirmed the proliferation of conventional methods incorporate cleavable linkages CD8 T cells for both wild type balb/c and OVA- of different densities positioned at single locations, transgenic-1 (OT-1) mice. Antigen specific immune such as the micellar core or the interface between response was obtained in WT mice treated with hydrophobic core and coronas (Single location ligand (adsorbed) modified OVA-MPLA 0.18 iv SRD). COOH NPs. This formulation showed about 93% of Methods: Our research group has recently focused dividing populations in different generations. The on an effective SRD strategy that centers on the same formulation secreted the highest amount of development of new intracellular nanocarriers IFNγ (12.94 ng/ml), IL-2 (1294.22 pg/ml), TNF-α having multiple stimuli-responsive cleavable (4566.21 pg/ml) and IL-6 (1299.66 ng/ml). In linkages at multiple locations, as in the micellar contrast, OVA-transgenic mice showed 81.1% of core, in the interlayered corona, and at the interface dividing population after re-stimulation with 20 between the hydrophobic core and corona (denoted times lower dose of OVA-peptide. The cytokines as ML-MSRD strategy). A typical dynamic linkage secreted were IFNγ (25.03 ng/ml), IL-2 (1890.94 is a disulfide bond that can be cleaved to pg/ml), IL-6 (1691.62 pg/ml) and TNF-α (3862.19 corresponding thiols in a reducing environment. In pg/ml) by covalently modified OVA-MPLA COOH biological systems, the reducing agent glutathione NPs. occurs at different concentrations in intracellular Conclusion: In conclusion, the findings confirm that versus extracellular environments; importantly, in PLGA NPs carrying cancer antigens are able to cancer cells levels are elevated. Other biocompatible produce antigen specific immune responses. This stimuli include acidic pH, enzymes, and light. response could be generalized to any type of cancer Results and Conclusions: This new strategy depending on the antigen loaded in NPs, which dramatically increases versatility since responses to could be considered a vaccine for a wide range of each stimulus can independently and precisely cancer types. regulate release of encapsulated biomolecules at several locations. Further, the strategy enables the investigation of structure-property relationship 20. Multi-location Multiple Stimuli-Responsive between morphological variance and stimuli- Degradation: A New Strategy for Accelerated responsive degradation. Ultimately, the results Drug Release and Cancer Therapy enable the optimization of degradable micelles offering enhanced release inside diseased cells, Nicky Chan, Na Re Ko, So Young An, Tongbing particularly targeted cancer cells. Sun, Arman Moini Jazani, Jung Kwon (John) Oh, Department of Chemistry and Biochemistry, Concordia University, Montreal, QC

Purposes: Well-defined amphiphilic block copolymers and their self-assembled nanostructures designed with stimuli-responsive degradation (SRD) have been extensively explored as a choice of promising nanocarriers for pharmaceutical science

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21. In Vitro and In Vivo Characterization of tabletted microparticles for VG. Tabletted Spray-Congealed Lipid Microparticles for Extended Release of Vildagliptin 22. Novel Application of siRNA-PEI Encapsulated Nanoparticles in Preventing Khaled Al Zahabi1, Loay Saifan1, AlSayed Sallam2 Vaginal Infection of Chlamydia Trachomatis and Husam M.Younes1 via PDGFR- β Knockdown and Autophagy 1Pharmaceutics & Polymeric Drug Delivery Induction Research Laboratory, College of Pharmacy, Qatar University, Doha, Qatar; 2Al-Taqaddom Celine Jimenez, Sidi Yang, and Emmanuel A. Ho Pharmaceutical Ind., Amman, Jordan Laboratory for Drug Delivery and Biomaterials, College of Pharmacy, Faculty of Health Sciences, Purpose: The spray-congealing (SC) microparticles University of Manitoba, Winnipeg, Manitoba, preparation technique was used to design an Canada extended-release oral tablet for Vildagliptin (VG) to be administered once daily in treatment of type-2 Purpose: The aim of this study was to evaluate the diabetes mellitus. novel application of small interfering RNA(siRNA)- Methods: Gelucire 50/13 and compritol lipid polyethylenimine (PEI) encapsulated nanoparticles carriers were heated at 10 oC above their melting (NPs) in preventing vaginal infection of chlamydia points. VG and Carbomer were dispersed in the lipid trachomatis via the knockdown of platelet-derived molten mass and sprayed through the two fluid growth factor- β (PDGFR- β)(an irreversible binding nozzle of the Buchi spray-congealer. Produced VG receptor for chlamydia trachomatis and an loaded microparticles (MP) were compressed into autophagy-irrelevant gene) and the induction of tablets and further characterized for their autophagy. morphological characteristics, physicochemical Methods: siRNA was first condensed by PEI and properties, content analysis, in vitro dissolution and then co-encapsulated into NPs by double-emulsion in vivo bioavailability studies using nine mixed-bred evaporation method using the biodegradable dogs in a crossover study design. The quantitative polymer, poly(lactic-co-glycolic acid)-polyethylene analysis was done using a validated high pressure glycol (PLGA-PEG). liquid chromatography with a photodiode array PDA Results: Scramble siRNA-PEI NPs (256.3±7.8 nm) detector for in vitro results and mass detector MS could significantly induce autophagy in vaginal was utilized for the in vivo VG concentrations. epithelial cells (VK2/E6E7) upon a 48 hr treatment Results: VG microparticles were amorphous, of 1.34 mg/mL NPs (equivalent to 37.6 µg/mL of spherical in shape with a total yield of 76%. The VG PEI), evidenced by the increased level of autophagic content in the microparticles was found to be 98.8%. flux (>6 folds compared to naïve control) and The in vitro dissolution studies showed that VG was decreased level of LC3-B (>15% decrease compared released from the tableted particles in a sustained- to naïve control), while the free PEI at the same release fashion for up to 24 hours in comparison to concentration was unable to do so due to massive the immediate-release VG marketed tablets, which cell death. Moreover, free PEI (1 µg/mL; highest released the drug within 30 minutes. The release concentration that does not elicit cell death) and profile of the SC formulation was similar after a siRNA NPs without PEI (1.34 mg/mL) were not able storage period of 6 months. The in vivo to induce autophagy. The gene expression of three pharmacokinetics studies reported a Cmax, Tmax, T1/2 autophagy genes involved in early (VPS 34) and late and mean residence time of 118 ng/ml, 3.4 h, 5.3 h autophagic stages (UVRAG and TECPR-1) were and 9.8 h respectively for the spray-congealed significantly upregulated by 35%, 33% and 32% formulation with a significant difference when respectively, upon the induction of autophagy by compared to those of the immediate-release scramble siRNA-PEI NPs. The siRNA-PEI NPs marketed drug (147ng/ml, 1 h, 2.1 h and 2.8 h were rapidly and efficiently taken up by VK2/E6E7 respectively). The area under the peak (AUC) of the and caused siRNA transfection in 100% cell tested and the reference were not significantly population in as early as 3 hrs. siRNA-PEI NPs different. encapsulating siRNA targeting PDGFR- β (1.34 Conclusion: SC technology was successfully mg/mL) caused more than 60% gene knockdown in utilized for the preparation of extended-release VK2/E6E7 without decreasing cell viability or

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inducing pre-inflammatory cytokines (TNF-α, IL1-β, effect over free GEM (~2-fold) and saline control (8- IL-6, IL-8). to 10-fold) in an s.c. tumour model in vivo. Conclusions: We have found and evaluated a novel Conclusion: This work demonstrates how chemical application of siRNA-PEI NPs as a potential strategy modification to create a prodrug of a known in preventing vaginal infection of chlamydia hydrophilic drug can lead to improved loading, trachomatis. The downregulation of PDGFR- β can stability and drug delivery in vivo. help decrease the bacterial binding to vaginal epithelial cells and the induction of autophagy by the NP formulation itself can help eradicate the invaded 24. Stable Encapsulation of Poorly Water- bacteria from the cells. The two mechanisms may Soluble Drugs into Lipid Nanoparticles for play a synergistic role in the protection against Drug Delivery vaginal chlamydia trachomatis infection. Wei-Lun Tang and Shyh-Dar Li. Faculty of Pharmaceutical Sciences, University of 23. Synthesis of a Gemcitabine Prodrug for British Columbia, Vancouver, BC, Canada Remote Loading into Liposomes and Improved Therapeutic Effect Purpose: Poor aqueous solubility has hampered efficient delivery of many drugs. This study is to Jonathan P. May and Shyh-Dar Li. develop a new remote loading method (Fig.1) that Faculty of Pharmaceutical Sciences, University of enables efficient and stable loading of poorly water- British Columbia, Vancouver, Canada soluble drugs into lipid nanoparticles (LNPs) to improve drug delivery. Purpose: Liposomal nanoparticles can provide an Method: A small amount of DMSO (normally 2- effective way to passively target the drug payload to 10% vol) was included during the remote loading a tumour and circumvent associated side effects. For process to prevent drug precipitation and facilitate such a treatment to be effective a sufficient quantity the loading of poorly water-soluble drugs of drug must be loaded with adequate stability in the (staurosporine (STS), a pan-tyrosine kinase inhibitor aqueous core of the liposome. A remote loading or mefloquine (MEF), an antimalarial drug) into the strategy can be used to achieve this, which relies aqueous core of LNPs composed of upon the drug being an amphipathic compound DSPC/cholesterol (55/45, molar ratio) with an possessing an ionizable functional group. ammonium sulfate gradient. DMSO and un- Gemcitabine is not a suitable drug for this purpose encapsulated drugs were then removed by dialysis. because it is relatively hydrophilic and has no Both STS-LNPs and MEF-LNPs were characterized suitable ionizable moiety. Here we report an by their size, drug-to-lipid ratio, and drug release innovative approach to actively and stably load kinetics. The safety and antitumor efficacy of the gemcitabine into lipid nanoparticles through the STS-LNPs were compared with free STS in a mouse formation of a pro-drug. model. The palatability and bioavailability of MEF- Method: Gemcitabine was chemically modified to LNPs were compared with a standard MEF introduce more lipophilicity and a weak base moiety suspension. for remote loading. Several derivatives were Results: A high drug loading efficiency with a drug- synthesized and the solubility, stability, cytotoxicity to-lipid ratio of 0.31-0.36 (mol/mol) was achieved and loading efficiency of these were screened for for both STS and MEF. Drug molecules of STS and their potential to be good liposomal remote loading MEF formed nano-aggregates inside the LNPs, and drug candidates. were stably retained inside the LNPs upon storage at Results: Two morpholino derivatives of 4°C. A 3-fold higher dose of the STS-LNPs was gemcitabine were chosen as the preferred prodrugs tolerated by BALB/c mice compared with free STS, for this purpose as they possessed the best loading leading to nearly complete growth inhibition of a efficiencies (100% for drug-to-lipid ratio of 0.36 multidrug resistant breast tumor, while free STS w/w). This is a considerable improvement over a only exhibited moderate activity. No drug release for passive loading strategy where typical loading MEF-LNPs was observed in the saliva-mimicking efficiencies are often in the order of ~10-20% for a medium for >2 h at 37°C, while the drug release is drug-to-lipid ratio of ~0.01. Liposomes loaded with rapid in simulated gastric fluid (>60% in 30 min) these two prodrugs showed improved therapeutic and intestinal fluid (>85% in 30 min). The bitter

From Drug Discovery to Health Outcomes: Population to Patient | 75s

taste of MEF was completely masked by the LNP buffer and then mixed with selected copper formulation, and the MEF-LNPs exhibited complexing compound. Formation of the copper- comparable bioavailability in mice compared to the drug complexes (CDCs) within the vesicles was standard MEF suspension measured spectrometrically. Conclusion: This simple and efficient drug loading Results: Formation of Cu(DDC)2 inside lipid method produced a stable LNP formulation for vesicles was readily detected when DDC was added delivering poorly water-soluble drugs, including to the outside of Cu-containing liposomes as the STS and MEF. solution colour changed from bluish white to dark brown. The Cu(DDC)2 synthesis reaction occurs in less than 5 min and the stoichometric relationship between Cu2+ and DDC inside the liposomes was determined to be 1:2. This approach was used to prepare formulations of Cu-Clioquinol, Cu- Quercetin, and Cu-CX5461 (a targeted drug). Preliminary safety and pharmacokinetic studies in mice demonstrate that the resulting formulations can

be administered intravenously. For the Cu(DDC)2 Figure 1. The principle of the solvent-assisted formulation the maximum tolerated dose was 8 loading technology (SALT) mg/kg i.v. Q2Dx14. Conclusion: Our method provides a simple yet transformative solution enabling, for the first time, 25. Nanoscale Reaction Vessels Designed for the development of CDCs as viable candidate Synthesis of Copper-drug Complexes Suitable anticancer drugs. These drugs would represent a for Preclinical Development brand new class of therapeutics for cancer patients.

M. Wehbe1,2, M. Anantha1, I. Backstrom1, A. 1,2 1,2 1 3 Leung , K. Chen , A. Malhotra , K. Edwards and 26. Mechanism of Low Density Lipoprotein 1,2,4, M.B. Bally Packaged Docosahexaenoic Acid Induced 1 British Columbia Cancer Research Centre Toxicity of Hepatic Cancer Stem Cells and 2 3 University of British Columbia University of Mature Cancer Cells 4 Uppsala Center for Drug Research and

Development, Vancouver, BC Jiaqi Yang1, Yuewen Gong1, Ian Corbin2, Gerald Y. Minuk3 Purpose: Copper-drug complexes (CDCs) are an 1Faculty of Pharmacy, University of Manitoba, interesting class of new anticancer agents, some of Canada, 2Advanced Imaging Research Center, which appear to be activated in the presence of University of Texas Southwestern Medical Center, copper to kill cancer cells. Even though some CDCs the United States, 3Section of Hepatology, are more potent than platinum based cancer drugs University of Manitoba, Canada (e.g. cisplatin) they have not successfully transitioned into the clinic because of their very poor Purpose: It has been suggested that cancer stem aqueous solubility. We have developed a method to cells (CSCs) within hepatocellular carcinoma (HCC) prepare CDCs inside lipid vesicle (liposomes) are responsible for hepatic tumour development and whereby the resulting product remains in solution. growth. We have successfully isolated and identified Copper bis-diethyldithiocarbamate (Cu(DDC)2) was CSCs from human Huh-7 and HepG2 HCC cell used as a model drug and the synthesis method was lines. We then employed the CSCs and residual successfully demonstrated using other copper- “mature” cancer cells (MCCs) in experiments complexing compounds. designed to document the cytotoxicity and Method: Lipid vesicles with encapsulated 300 mM generation of reactive oxygen species (ROS) CuSO4 were prepared from phosphatidylcholine following exposure to low-density lipoprotein (LDL) (PC) and cholesterol (Chol) (55:45 mole ratio). packaged docosahexaenoic acid (DHA) (LDL-DHA) Using extrusion methods, the diameter of the nanoparticles, a newly proposed treatment for HCC. vesicles was adjusted to ~100 nm. The buffer on the Methods: CSCs and MCCs isolations were achieved outside of the vesicles was changed to a pH 7.4 by fluorescence-activated cell sorting utilizing

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epithelial cell adhesion molecule (EpCAM) and Methods: IRB-syringic acid eutectic solid form CD133 stem cell markers. Dose- and time-dependent (ISA-ESF) was prepared by mechnochemical cell cytotoxicity was determined by the WST-1 approach. Initial screening was performed by DSC assay. Cellular ROS levels were evaluated by (differential scanning calorimeter) and PXRD H2DCFDA. (powder-X ray diffraction) techniques. ISA-ESF was Results: Isolated EpCAM+CD133- Huh-7 and assessed for their physicochemical studies. HepG2 cells (CSCs) exhibited the capacity of self- Antioxidant and In vivo antihypertensive activity renewal, tumorigenesis and migration, while were investigated in dexamethasone induced EpCAM-CD133- (MCCs) failed to do so. After hypertensive rats. Pharmacokinetic profile of ISA- exposure of CSCs and MCCs derived from Huh-7 ESF was also performed in male Wistar rats. cells to LDL-DHA nanoparticles, there were dose- Results: DSC result of ISA-ESF shows single and time- dependent effects on cell cytotoxicity. At a endothermic event at 162 °C which is lower than concentration of 40μM, LDL-DHA eradicated CSCs both components. Excess enthalpy of fusion of ISA- and MCCs within 48 hours of exposure. However, ESF shows its thermodynamic stability. ISA-ESF LDL-DHA nanoparticles only had a minimal effect exhibited higher aqueous solubility (9 times) and on CSCs and MCCs derived from HepG2 cells. improved intrinsic dissolution rate (2 times) than the After two hours of LDL-DHA exposure, high levels pure crystalline IRB. ISA-ESF showed significant of ROS were detected in CSCs and MCCs from both reduction in plasma hydrogen peroxide Huh-7 and HepG2 cells. concentration and strongly reduced systolic blood Conclusion: In Huh-7 cells, LDL-DHA pressure in hypertensive rats as compared to pure nanoparticles are equally toxic to both CSCs and drug (p< 0.01). In vivo pharmacokinetic study also MCCs. However, CSCs and MCCs derived from revealed marked improvement in the drug absorption HepG2 cells tend to be resistant to such treatment, parameters (Cmax, AUC) as compared to free drug despite the induction of similar degrees of oxidative suspension. stress. Conclusion: In nutshell, the present study successfully demonstrated improved biopharmaceutical performance along with 27. Eutectic Solid Form of Irbesartan-Syringic antioxidant activity of eutectic solid form of IRB acid: Mechanistic Evaluation of prepared with syringic acid for effective Thermodynamic Properties, Solid State management of hypertension. Characterization and In Vivo Studies

Jamshed Haneef and Renu Chadha, 28. Microfluidics-Based Manufacture of Size- University Institute of Pharmaceutical Sciences, Tunable Liposomes for the Delivery of Small Panjab University, Chandigarh Molecule Therapeutics

Purpose: Aqueous solubility of BCS II class drugs Anitha Thomas, Shyam Garg, Jagbir Singh, Gesine is the key determinant of their oral bioavailability. Heuck, Shell Ip, Tim Leaver, Andre Wild, James Eutectic solid forms (ESFs), in this regard, have Taylor, Euan Ramsay. gained wide attention among pharmaceutical Precision NanoSystems, Inc., Vancouver, BC, scientists to overcome this challenge. One of the Canada peculiar properties of ESFs is that they have low melting point owing to depletion in crystal packing Purpose: Conventional methods for the production energy of binary components resulting in enhanced of liposomes are labor-intensive and pose numerous dissolution rate and thereby improved challenges in controlling liposome size, scale-up, bioavailability. The aim of present investigation was and reproducibility. The NanoAssemblr™ to prepare ESF of irbesartan (IRB) which is a potent microfluidic platform can eliminate user variability long acting non-peptide angiotensin-II receptor and is capable of rapid, reproducible, and scalable antagonist with low aqueous solubility (< 0.1 manufacture of liposomes. Here, we describe the use mg/mL). Syringic acid (SA) was selected as second of microfluidic mixing to manufacture liposomes of component because it belongs to phenolic defined size and compositions. antioxidant class that exert good cardio-protective Methods: Liposomes were manufactured using the effects. NanoAssemblr™ bench-top instrument (Precision

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NanoSystems, Inc., Vancouver, Canada). Lipids using the microfluidics-based NanoAssemblr™ such as POPC, DSPC, Cholesterol, and pegylated- platform. We further describe the delivery of PTEN lipid were dissolved in ethanol at varying siRNA-LNPs into neurons both in vitro and in vivo. compositions and concentrations. Liposomes were Methods: LNPs containing a potent siRNA directed formed by nanoprecipitation achieved by the rapid against PTEN were prepared using the and controlled mixing of two-inlet fluid streams NanoAssemblr™ bench-top instrument (Precision containing lipids in ethanol and aqueous buffers, NanoSystems, Inc., Vancouver, Canada). PTEN is a through proprietary staggered herringbone mixing clinically relevant gene associated with neural (SHM) apparatus. regeneration. The siRNA-LNPs were characterized Results: Microfluidic mixing enabled the rapid and for their encapsulation efficiency using Ribogreen consistent manufacturing of liposomes having Assay. In vitro studies for PTEN gene knockdown diameters ranging from 25 – 150 nm depending on were conducted in primary mixed cortical neuronal variables such as aqueous:organic flow rate ratio, cell cultures using qPCR. The efficacy of LNPs was and lipid composition. Liposomes consisting of tested in vivo following local administration of saturated DSPC prepared through microfluidics PTEN siRNA-LNPs in the brain and spinal cord of exhibited a higher size as compared to liposomes Sprague Dawley rats. prepared using an unsaturated lipid such as POPC at Results: LNPs manufactured using the microfluidics similar aqueous:organic flow rate ratios. Liposomes platform exhibited a small size (~50 nm), low PDI prepared using microfluidics were similar in size at (<0.1), and high PTEN siRNA encapsulation concentrations ranging from 10 – 75 mg/mL, efficiency (>95 %). In primary mixed cortical indicating the ability of the system to show neuronal cell cultures, LNPs mediated a sustained consistent and reproducible results within a certain (>80 %) knockdown in PTEN gene expression at range of lipid concentrations. low doses of 100 ng/mL for up to 21 days. Conclusions: Herein, we have shown the potential Controlled localized injections of PTEN siRNA- of liposomes manufactured using the microfluidic LNPs into the motorcortex resulted in significant platform to be used as carriers for small molecule and sustained knockdown (7 days). Similarly, local therapeutics. administration at the site of spinal cord injury significantly decreased PTEN expression 10 days later. 29. Microfluidics-based Manufacture of RNA- Conclusions: This study reflects the potential of this Lipid Nanoparticles as Potent Delivery delivery vector for use in the screening and Vectors for Manipulating Gene Expression In validation of new nucleic acid therapeutics in Vitro and In Vivo neuroscience.

Eric Ouellet1, Grace Tharmarajah1, Dounia Droubi1, Shyam Garg1, Oscar Seira2,3, Jie Liu2,3, Anitha 30. Complete Regression of Xenograft Tumors Thomas1, Tim Leaver1, Andre Wild1, Yuping Li4, upon Targeted Delivery of Paclitaxel via Π-Π Yu Tian Wang4, Wolfram Tetzlaff2,3, Pieter Cullis5, Stacking Stabilized Polymeric Micelles James Taylor1, Euan Ramsay1. 1Precision NanoSystems, Inc., Vancouver, BC, Canada. Roy van der Meel1,2, Yang Shi3,4, Benjamin Theek5, 2International Collaboration on Repair Discoveries Erik Oude Blenke3, Ebel H.E. Pieters3, Marcel (ICORD), 3Department of Zoology, 4Brain Research H.A.M. Fens1, Josef Ehling5, Raymond M. Center, 5Biochemistry and Molecular Biology, Schiffelers1, Gert Storm3,6, Cornelus F. van University of British Columbia, Vancouver, BC, Nostrum3, Twan Lammers3,5,6, Wim E. Hennink3 Canada 1University Medical Center Utrecht, The Netherlands; 2University of British Columbia, Purpose: Recently, lipid nanoparticles (LNPs) have Vancouver, BC, Canada; 3Utrecht Institute for gained interest as efficient carriers for nucleic acids Pharmaceutical Sciences, Utrecht University, The both in vitro and in vivo. However, their transition Netherlands; 4South China University of from bench to clinic has been slow due to numerous Technology, Guangzhou, Guangdong, China; challenges such as poor reproducibility and 5Helmholtz Institute for Biomedical Engineering, scalability. Here, we bridge that gap by describing RWTH Aachen University Clinic, Aachen, the robust and scalable manufacture of siRNA-LNPs Germany; 6MIRA Institute for Biomedical

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Technology and Technical Medicine, University of by the China Scholarship Council, the European Twente, Enschede, The Netherlands. Research Council (ERC Starting Grant 309495: NeoNaNo) and the German Research Foundation Purpose: Improve the therapeutic index of (DFG: LA 2937/1-2). paclitaxel (PTX) by encapsulation in π-π stacking References: 1. Shi Y. et al. ACS Nano. (2015) stabilized micelles formulated without chemical 9(4):3740-52. cross-linking or covalent drug attachment for tumor- targeted drug delivery [1]. Methods: PTX-loaded polymeric micelles were 31. Development of a Stable Liposomal prepared by dropwise adding of THF solution Isotretinoin for Drug Delivery containing (methoxy poly(ethylene glycol)-b-(N-(2- benzoyloxypropyl) methacrylamide)) (mPEG- Wei-Hsin (Sophia) Tang, Wei-Lun Tang, and Shyh- bp(HPMAm-Bz)) polymer and PTX into water Dar Li. Faculty of Pharmaceutical Sciences, followed by evaporation of THF. The University of British Columbia, Vancouver, British physicochemical characteristics of the PTX-loaded Columbia, Canada micelles were analyzed and effects on tumor cell viability in vitro were determined by XTT assays. Purpose: The aim of this study was to develop a Pharmacokinetics (PK) and biodistribution (BD) of stable liposomal formulation of a water-insoluble fluorescent-labeled micelles and model drug after drug, isotretinoin (ITT), for efficient and safe drug intravenous (iv) administration in tumor-bearing delivery. mice were determined using multimodal imaging Method: The minimal amount of DMSO, required techniques as well as PTX UPLC analysis. for complete drug solubilisation, was determined by Therapeutic efficacy of the PTX-loaded micelles solubility test (1). The main purpose of was determined in two human tumor xenograft incorporating DMSO into this remote loading models (A431 and MDA-MB-468) in mice. process is to prevent drug precipitation and facilitate Results: Micelles ranged between 80-100 nm (PDI the loading of ITT into the liposomal core. <0.15) in size and showed high encapsulation Subsequently, the determined amount of DMSO was efficiency (> 80%). Inhibition of tumor cell viability added to the preformed DSPC/cholesterol (55/45, induced by PTX-loaded micelles was similar to molar ratio) liposomes with a calcium formate Taxol®. Multimodal imaging demonstrated closely gradient. DMSO and un-loaded drugs were then associated PK/BD of the labeled micelles and model removed by spin column. Additional optimization of drug as well as substantial tumor accumulation 48h the liposomal ITT was conducted by varying drug- post injection. The half-life of PTX encapsulated in to-lipid ratio and incubation time. To characterize micelles was significantly increased (∼8 h) when the liposomal ITT formulation, size, loading compared to that of Taxol®. PTX could not be efficiency, drug release kinetics (in simulated detected 24h post injection in the tumors of mice gastric, intestinal fluid, and saliva), and storage that received PTX formulated in control micelles or stability were determined. Taxol®. In contrast, high concentration of PTX in Results: 5% DMSO in borate buffer (v/v) was tumors (∼8 ID%/g) of mice that received PTX- required for efficient drug loading, as its presence loaded mPEG-bp(HPMAm-Bz) micelles was increased the solubility of ITT (<5 µg/mL in water) detected correlating with the results of the imaging significantly by 300-fold. 100% drug encapsulation study. Repeated injections of PTX-loaded micelles of ITT in liposomes was achieved at 5% DMSO and were well tolerated at doses of 15-30 mg/kg. In both a drug-to-lipid ratio of 0.1-0.2 (weight ratio), within tumor xenograft models, treatment with Taxol® (15 35 min at room temperature. The particle size of the mg/kg) had little or no effect on tumor growth, while liposomal ITT was ~110 nm (PDI < 0.1). Drug the PTX-loaded micelles (15-30 mg/kg) induced release kinetics study is ongoing and will be finished complete tumor regression. in April. Storage stability will be monitored for at Conclusions: Polymeric micelles stabilized by π-π least 6 months. stacking interactions are considered to be an Conclusion: An effective and stable ITT attractive platform for improving PTX or other encapsulation into liposomes, achieved by the highly hydrophobic drug delivery to tumors and to solvent-assisted remote loading, may improve poor increase their therapeutic index. drug delivery of ITT. Acknowledgements: This research was supported Reference: 1. Tang WL, Chen WC, Roy A, Undzys

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E, Li SD. A Simple and Improved Active Loading 20 nm particles displayed significantly enhanced Method to Efficiently Encapsulate Staurosporine tumor penetration compared to the larger into Lipid-Based Nanoparticles for Enhanced counterparts. Therapy of Multidrug Resistant Cancer. Pharm Res. References: [1] A. I. Minchinton, et al. (2006). Nat. 2016 Jan 12. Rev. Cancer 6, 583-592; [2] V. P. Chauhan, et al. (2011). Phil. Mag. 2, 281-298; [3] R. Aniruddha, et al. (2015). Biomaterials 52, 335-346 32. Intratumoral Penetration by a Nanoparticle of Podophyllotoxin on Tumor Spheroids and In vivo Tumor Models 33. Development of a Segmented Intravaginal Ring for the Combination Delivery of Yang Yang , Aniruddha Roy, Shyh-Dar Li. Hydroxychloroquine and siRNA- Faculty of Pharmaceutical Sciences, The University encapsulated Nanoparticles as a Novel of British Columbia, Vancouver, British Columbia, Strategy for Preventing HIV Infection Canada Yannick L. Traore, Vincent Jimenez, Fernanda Purpose: Poor intratumoral penetration in solid Padilla, Emmanuel A. Ho tumors has been one of the major challenges limiting Laboratory for Drug Delivery and Biomaterials, the antitumor efficacy of nanomedicines [1, 2]. We College of Pharmacy, Faculty of Health Sciences, have developed a polysaccharide conjugate University of Manitoba nanoparticle system for drug penetration to solid tumors. Purpose: We developed and characterized a Methods: Podophyllotixin (PPT, an anti-tubulin segmented intravaginal ring (IVR) capable of drug) and polyethylene glycol (PEG) were delivering two different compounds. The first covalently conjugated to acetylated carboxymethyl segment is coated with a pH-sensitive polymer cellulose (CMC-Ac) via ester linkages [3]. We containing small interfering RNA (siRNA)-loaded examined how PPT-to-PEG ratio in the conjugate nanoparticles. The siRNA-loaded nanoparticles affected properties of the resulting nanoparticles and (siRNA-NP) will be released only when the pH of compared their penetration in a tumor spheroid the female genital tract increases to greater than pH system and an s.c. tumor in mice. 6.5 due to the presence of seminal fluid. The second Results: The size of the resulting nanoparticles segment contains hydroxychloroquine (HCQ), an increased with the increased PPT/PEG ratio. The immuno-modulatory drug that will be released in a conjugate of a PPT/PEG ratio of 20 yielded 120 nm sustained and controlled manner. particles, while 20 nm particles were produced with Methods: Poly(lactic-co-glycolic acid)-polyethylene the conjugate of a PPT/PEG ratio of 2. The drug glycol (PLGA-PEG) was used to encapsulate siRNA release rates for the 20, 30 and 120 nm particles using the double emulsion method to form were 5%, 2.5% and 1%/day, respectively. The 20 nm nanoparticles (siRNA-NP). siRNA-NP was mixed particles exhibited 2- to 5-fold enhanced cell killing with a pH-sensitive polymer (Eudragit L100) activity and 5- to 20-fold increased delivery to an dissolved in isopropanol, and used to coat a matrix- s.c. tumor compared to the 30 nm and 120 nm type IVR segment, fabricated by injection molding particles. In tumor spheroids, the tumor penetration from polyurethane. A release study was performed efficiency of the nanoparticles followed the order of in vaginal fluid simulant at basic and acidic pH. 20 nm > 30 nm > 120 nm. The 20 nm particles HCQ was loaded in a reservoir-type IVR segment penetrated the EMT6 tumor spheroids thoroughly in and an in vitro release study was performed in 3 h, while the 120 nm particles displayed little sodium acetate buffer (pH 4.2). The biocompatibility penetration. The in vivo data were consistent with of the IVR segments was evaluated on vaginal the spheroid data: within the s.c. tumor, >90% of the epithelial cell lines VK2/E6E7 and ECT1/E6E7 and 20 nm particles penetrated to the hypovascular core, on vaginal flora Lactobacillus crispatus and jensenii. while the larger particles were largely restricted in Results: IVR segments coated with a pH-sensitive the hypervascular periphery. polymer rapidly released siRNA-NP at pH8.2 but Conclusion: By varying the PPT/PEG ratio in the not at pH 4.2. The reservoir-type IVR segment conjugates, nanoparticles with different containing HCQ continuously released drug up to 21 physicochemical properties could be prepared. The days with a near zero-order release profile (R2 value

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=0.99). Cytotoxicity evaluation of IVR segments on Results: In vitro release and ex vivo permeation of vaginal cells and lactobacilli demonstrated no LL37-A1-SLNs followed a biphasic pattern with an changes in cell viability or bacteria growth, intial release of >10% by day 1. Precise combination respectively. ratios exhibiting synergy against S. aureus and E. Conclusion: We developed and characterized a coli were determined. LL37-A1-SLNs demonstrated segmented IVR that can deliver HCQ over 21 days faster WH by day 13 with better granulation tissue and rapidly released siRNA-NP only at pH 8.2. The formation, denser and compact collagen deposition IVR segments are non-cytotoxic towards vaginal and and higher endothelial cell colonization in bacterial cells. comparison to controls or individual treated groups. Conclusion: This is the first study to develop a nanoparticle formulation for the combination 34. Topical Nanoformulation for the delivery of LL37 and A1 as strategy for the Combination Delivery of Peptides for treatment of CWs. Accelerated Wound Healing and Synergistic Antibacterial Activity 35. Poly (oligoethylene glycol methacrylate)- Miral Fumakia and Emmanuel A. Ho block-poly (D, L-lactide)-based Nanoparticles College of Pharmacy, University of Manitoba, as Versatile Hydrophobic Drug Delivery Winnipeg, MB, Canada Vehicles

Introduction: Chronic wounds (CWs) are a serious Maryam Badv1 and Todd Hoare1,2 health care concern as they fail to resolve and are 1School of Biomedical Engineering; 2Department of characterized by “non-resolving” chronic Chemical Engineering, McMaster University, inflammatory state. Most current therapies target Hamilton, ON, Canada only single aspect of the CW process making it difficult to achieve effective healing hence, a new Introduction: Polymeric nanoparticle (NP) drug paradigm towards development of combination delivery systems, particularly NPs formulated from therapies for CWs is urgently required. Serpin A1 is the block copolymer poly (ethylene glycol)-b-poly a powerful anti-inflammatory and (lactic acid) (PEG-b-PLA) have shown great clinical immunomodulatory agent in CW healing. LL37 is a potential given their high biocompatibility and host defense peptide possessing anti-infective and degradability. However, the single end functional wound healing properties. Thus, the combination group on PEG poses limitations on the use of these delivery of these peptides (LL37-A1) using solid materials for emerging ligand-receptor targeting lipid nanoparticles (SLNs) may potentially systems. Herein, we address this limitation by accelerate wound healing as well as demonstrate replacing the PEG block with poly (ethylene glycol synergistic antibacterial activity. methacrylate) (POEGMA) that has a methacrylate Objective: To evaluate LL37-A1-SLNs as a backbone and PEG side-chains. POEGMA has been potential combination strategy for accelerated shown to have similar physical and biological wound healing and synergistic antibacterial properties to PEG but can be copolymerized, properties. enabling facile multi-ligand grafting. In addition, Methods: SLNs encapsulated with LL37-A1 were POEGMA can be engineered to be a “smart” fabricated using solvent-diffusion double emulsion polymer for drug delivery, exhibiting a lower critical technique. In vitro release and ex vivo permeation solution temperature (LCST) by changing the length studies were performed in artificial wound fluid pH of the oligoethylene glycol side chains, enabling 7.4. Synergy was evaluated against S. aureus and E. potential microenvironment-responsive NP delivery. coli using the Chou-Talalay method. The WH Methods: Fluorescently labeled (Cy5) PLA-b- property was investigated in murine Balb/c mice P[OEGMA-co-M(EO)2MA] block copolymers were model over a period of 13 days and % wound prepared using PLA-Br as a macroinitiator for atom closure was determined. Histological assessment transfer radical polymerization of the OEGMA was performed in order to determine the comonomers. Doxorubicin (DOX)-loaded NPs were predominant stages, extent of collagen deposition prepared by solvent exchange and characterized with and formation of blood vessels during the healing dynamic light scattering and transmission electron process. microscopy. Drug loading and release kinetics were

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tracked using UV/vis spectrophotometry. NP uptake examined at 370.5 C in rat plasma. into MCA205 tumor cells was assayed via confocal Results: The DFN and DFEE loaded polymeric microscopy. micelles exhibited particle size in the range of 27.9- Results: The block copolymers exhibited narrow 50.3 nm and narrow size distribution. The slowest molecular weight distributions (PDI <1.13) and release for DFN micelles was achieved with micelles well-defined compositions. The resulting self- of PEO-block-poly(α-carboxyl-ε-caprolactone) with assembled NPs were ~50 nm in size and exhibited a a side chain of N,N-dimethyldipropylenetriamine well-defined LCST. NPs were loaded with DOX which showed 713.2% drug release in 4 h followed with high encapsulation efficiencies (72%) and by a sustained drug release reaching 100% within 24 enabled prolonged drug release kinetics. PLA-b- h. The DFEE micelles showed slower release in P[OEGMA-co-M(EO)2MA] NPs did not show comparison to DFN, and the optimal results were significant cytotoxicity via an MTT assay-based in achieved with PEO-poly(ε-caprolactone) micelles vitro cell assay. In vitro studies to investigate the cell with percent release of 6.84.7% of the drug in 4 h uptake of the NPs are underway and will be and 10.82.9% in 24 h. Incubation with plasma of reported. polymeric micellar DFEE for 48 h revealed slow Conclusion: PLA-b-P[OEGMA-co-M(EO)2MA]- appearance of DFN as compared to that with the free based NPs offer a more versatile delivery platform DFEE and a good correlation with in vitro DFEE compared to conventional PEG-PLA NPs with the release data. potential to enable environmentally-responsive Conclusion: The results show a great potential for targeting and drug release. polymeric micelles in passive targeting of DFEE in inflammation.

36. Polymeric Micelles for Targeted Delivery of Diclofenac and its Ethyl Ester Derivative in 37. Modification of Polymeric Micellar siRNA Inflammation Delivery Systems with Breast Tumor Selective Peptide Ligands: Towards Hanan Al Lawati, Mohammadreza Vakili, Development of Breast Tumor Targeted Fakhreddin Jamali, and Afsaneh Lavasanifar. siRNA Nano-delivery Systems Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada Igor Paiva1, Mohammad Vakili1, Rania Soudy1, Kamaljit Kaur2, Afsaneh Lavasanifar1. Purpose: Inflammatory conditions such as arthritis 1Faculty of Pharmacy and Pharmaceutical Sciences, cause cardiovascular (CV) complications. Ironically, University of Alberta, Edmonton, AB, Canada; nonsteroidal anti-inflammatory drugs (NSAID)s that 2School of Pharmacy, Chapman University, Irvine, are given to treat inflammation, can cause CV CA, 92618, United States complications upon long term use, as well. Previous studies show high drug distribution to organs such as Purpose: The long term objective of this study is to heart and kidney can play a role in the emergence of develop tumor targeted siRNA delivery systems. CV side effects by NSAIDs. The aim of this study Here, we explored development of polymeric is to develop a polymeric micellar formulation to micellar systems for siRNA delivery modifying their limit distribution into heart and kidneys of surface with an engineered peptide, P18-4, which diclofenac (DFN), an NSAID with known CV has shown high stability in biological fluids and toxicity. Such formulation is expected to reduce CV selectivity for breast cancer over normal cells in side effects of DFN. previous studies. Methods: DFN and diclofenac ethyl ester (DFEE) Methods: Poly(ethylene oxide)-b-poly(α-carboxyl- were encapsulated in polymeric micelles prepared ε-caprolactone) (PEO-PCCL) and acetal-PEO-PCCL from several block copolymers based on methoxy were synthesized and used to conjugate (through poly(ethylene oxide)-poly(ester)s (PEO-poly(ester)s. their pendent carboxyl groups) spermine (SP) or Prepared micelles were characterized for their N,N-dimethyldipropylenetriamine (DP) producing particle size, polydispersity, encapsulation PEO-P(CL-SP), PEO-P(CL-DP) and acetal-PEO- efficiency, drug loading content, and in-vitro drug P(CL-DP) block copolymers. A 2:1:1 (w/w) of the release. The kinetics of enzymatic hydrolysis for above polymers was used to prepare polymeric DFEE micelles versus free DFEE was, then,

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micelles for P18-4 conjugation through Schiff base used to determine cytotoxicity. Both cells were also reaction. Using gel electrophoresis, siRNA binding exposed to different concentration of free or and serum stability in the presence of FBS was liposomal DOX (Caelyx®) alone, for 24-48h and tested at different siRNA:polymer ratios for plain investigated for their viability by MTT assay. versus P18-4 modified micelles. siRNA release as a Finally, cells were pretreated with MCL-1 siRNA function of increasing heparin concentration was for 48h; and then treated with doxorubicin or also examined using 1:16 siRNA: polymer ratio. Caelyx® for an additional 24h. Viability of cells MDA-MB-435 cells were treated with 300 nM following combination treatment was compared to MCL-1 siRNA in a siRNA: polymer ratio of 1:8 and DOX or siRNA monotherapies. MCL-1 mRNA expression was measured by RT- Results: Free DOX presented a lower IC50 in breast PCR. cancer cells compared to the liposomal DOX, Results: Complete siRNA binding was achieved at because of the instant availability of free DOX for siRNA:polymer ratio of 1:8 for both plain and P18-4 cell uptake compared to controlled release of DOX modified micelles. At lower siRNA:polymer ratios and its slower cellular uptake as part of liposomal siRNA binding was less, but still no significant formulation. MDA-MB-435 cells were more difference in siRNA binding was observed between sensitive to DOX treatment compared to MDA-MB- plain and p18-4 modified micelles. However, siRNA 231 cells evidenced by ~ 40 times lower IC50 of dissociation from P18-4 micelles demanded a DOX in these cells. Treatment with MCL-1 siRNA smaller concentration of heparin. At siRNA:polymer reduced the MCL-1 mRNA expression by ~ 60 % in ratio of ≥ 1:8, around 100% of siRNA was protected both cell lines, but did not affect cell viability as against degradation in serum. There was no monotherapy. MDA-MB-231 cell viability in the significant difference between plain and peptide presence of DOX was not significantly affected by modified micelles in terms of siRNA stabilization MCL-1 silencing. However, MCL-1 siRNA pre- either. Plain and P18-4 modified polymeric micellar treatment made MDA-MB-435 cells more sensitive complexes of MCL-1 siRNA down-regulated the to free and liposomal DOX. expression of MCL-1 mRNA by 75 and 82%, Conclusions: The effect of MCL-1 down-regulation respectively, compared to their scrambled siRNA on the sensitization of breast cancer cells to controls. doxorubicin and Caelyx® is cell dependent. Conclusion: The results point to a potential for P18- 4 nano-micelles in siRNA delivery. 39. STK-01 a Novel Intravesical Therapy for Non-muscle Invasive Bladder Cancer 38. The Effect of MCL-1 Down Regulation on the Sensitization of Breast Cancer Cells to Clement Mugabe1, Richard Liggins1, Mike Parr2, Doxorubicin and Caelyx® Igor Moskalev3, Alan So3, Martin Gleave1, Jayachandran Kizhakkedathu4, Donald Brooks4, Igor Paiva and Afsaneh Lavasanifar. Helen M. Burt5 Faculty of Pharmacy and Pharmaceutical Sciences, 1Centre for Drug Research and Development, University of Alberta, Edmonton, Alberta, Canada Vancouver; 2Stika Biopharma Inc. 3Vancouver Prostate Centre, Vancouver; 4Centre for Blood Purpose: Increased expression of anti-apoptotic Research, Vancouver; 3Faculty of Pharmaceutical proteins is an important cellular mechanism against Sciences, University of British Columbia, chemotherapy effectiveness in cancer. Myeloid cell Vancouver, BC. leukemia 1 (MCL-1) is one of the most up-regulated proteins in doxorubicin-resistant breast cancer cell Purpose: Development of novel therapeutics for lines. The objective of this study was to investigate patients with high-risk non-muscle-invasive bladder whether MCL-1 down regulation affects doxorubicin cancer is an important topic considering the rather treatment in breast cancer cells. limited options currently available. We have Methods: MDA-MB-435 and MDA-MB-231 cells developed a functionalized nanoparticle formulation were exposed to 50 nM MCL-1 siRNA for 48h using of docetaxel to improve treatment outcomes of lipofectamine as transfecting agent. RT-PCR was intravesical chemotherapy. Our novel docetaxel used to quantify MCL-1 mRNA expression using formulation is based on hyperbranched polyglycerol GAPDH as housekeeping gene. MTT assay was (HPG) technology and has shown promising

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efficacy in treating non-muscle invasive bladder Alpha Healthcare has developed and validated a tumors in mouse xenograft models. The objective of simple and sensitive method for the simultaneous this study was to investigate the effect of intravesical determination of Oxybenzone, Octocrylene, dwell-time with STK-01 in an orthotopic non- Avobenzone Octinoxate, Homosalate and Octisalate muscle invasive bladder cancer model. in human Sunscreen Lotion by high-performance Methods: KU7 cells that stably express firefly liquid chromatography. luciferase (KU7-luc) were inoculated in female nude Method: Methanol was added to sunscreen lotion mice by intravesical instillation and quantified using samples containing Oxybenzone, Octocrylene, bioluminescence imaging. Mice with established Octinoxate, Avobenzone, Homosalate and Octisalate KU7-luc bladder tumors were given a single and agitated the sample until dissolved. After intravesical instillation with STK-01 (0.2 mg/ml dilution, filtered the sample preparation through 0.45 docetaxel HPG-NH2 formulation) with a dwell of um nylon filter and injected for analysis by high- 15, 30, or 60 min. Control mice were catheterized performance liquid chromatography. Separation was only without instillation. Tumor growth was achieved on a Zorbax SB-C18 (250 mm x 4.6 mm, 5 monitored by bioluminescence and ultrasound um) analytical column with a mobile phase of 80:20 imaging techniques. methanol:water. Detection was at 320 nm using an Results: STK-01 significantly inhibited tumor ultraviolet detector. The mean retention times of growth against KU7-luc orthotopic bladder cancer Oxybenzone, Octocrylene, Avobenzone, Octinoxate, xenografts in a dwell-time dependent manner. A cis-Homosalate, Octisalate and trans-Homosalate single intravesical therapy with STK-01 for 60 min were 5.4, 19.4, 23.4, 25.1, 27.7, 30.7 and 34.1 min, showed a near complete tumor inhibition in mice. respectively. Peak areas were fit to a least squares Conclusion: STK-01 was found to be safe and linear regression algorithm. effective in treating non-muscle invasive bladder Results: The method produces acceptable linearity tumors in mice. Our data show promising in vivo (r2= more than 0.999 for all analytes) precision antitumor efficacy and provide preclinical proof-of- (CV= less than 2% for all analytes) and accuracy principle for the intravesical therapy with STK-01. (recovery= 100+2.0% for all analytes) to a minimum concentration of 1.0 micrograms per ml in human sunscreen lotion. Conclusion: The method is very simple, rugged, and Pharmaceutical & Analytical convenient. It can be used to analyze six sunscreens in human lotion in a single run with no observable Chemistry matrix interferences.

41. Histone Lysine Methyltransferase Inhibitors Decrease HOXA9 Expression and Induce 40. Simultaneous Determination of Oxybenzone, Global Changes in Histone Post-translational Octocrylene, Avobenzone, Octinoxate, Modifications Homosalate and Octisalate in Human Sunscreen Lotion by High-performance Ryan Lillico and Ted M. Lakowski Liquid Chromatography with Ultraviolet Faculty of Health Sciences, College of Pharmacy, Detection Pharmaceutical Analysis Laboratory, The University of Manitoba, Winnipeg, Manitoba, Canada Masood Bhatti, Nalliah Theivendra and Teresa Del Rosario, Alpha Healthcare, Toronto, Ontario, Purpose: Histone lysine methyltransferase (HKMT) Canada inhibitors are emerging as treatment strategies for mixed lineage leukemia by decreasing expression of Purpose: Frequent exposure to UV radiation has the homeobox A9 (HOXA9) oncogene by pronounced harmful effects on human health. To modulating the methylation status of histones. Since prevent skin damage from the sun’s radiation, many HKMTs are found in all gene promoters, HKMT skin care products, such as lipstick, makeup, and inhibitors likely alter the expression of many genes. lotions contain one or more sunscreen compounds to We have observed similar issues with histone block UV radiation. The Industrial Pharmaceutical deacetlyase inhibitors. We hypothesize that HKMT Laboratories Division at the Toronto facility of inhibition will result in changes to unrelated

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epigenetic modifications and alter expression of off- Purpose: Phenanthridinones are one class of target genes. poly(ADP-ribose) polymerase (PARP) inhibitors Methods: Using LC-MS/MS we measured histone that have shown anti-cancer effects, and are typically modifications in MOLM13 cells over-expressing synthesized using inefficient batch cross-coupling HOXA9 treated with HKMT inhibitors EPZ4777, reactions. Flow chemistry has shown its benefits in EPZ5676 and BRD4770. Changes in HOXA9 performing chemical reactions efficiently and expression were measured using the Viia7 qPCR scaling up easily for industrial purpose without with predesigned TaqMan primers and probes. modifying reaction conditions. For the enhancement Histones were isolated with the EpiQuik histone of the drug discovery process, we found the isolation kit (Epigentek) and mRNA isolated with possibility to produce phenanthridinones with the Purelink RNA purification kit. photocyclization method under continuous flow Results: HKMT inhibitors of the human disruptor of conditions in a superior fashion to analogous batch telomeric silencing 1-like (DOT1L), EPZ5676 and chemistry methods. The aim of this study was to EPZ4777, are expected to decrease HOXA9 develop a flow-photocyclization method to expression by inhibiting H3K79 methylation, but synthesize phenanthridinones and demonstrate the treatment resulted in off-target increases in robustness and scaling-up ability of the method. acetyllysine (26.7±8.1% increase), dimethyllysine Method: A Vapourtec® E2+/E4 flow chemistry (24.7±10.5% increase) and symmetric dimethyl system equipped with a UV-150 photochemical arginine (25.3±2.8% increase), as well as decreases reactor was used to perform single-step flow in monomethyllysine (4.6±0.6% reduction), photocyclization reactions, starting from 2-chloro-N- trimethyllysine (21.4±1.7% reduction) and phenylbenzamides.The residence time (reacting asymmetric dimethylarginine (26.5±7.2% time) for the single-step reaction was 50 minutes. reduction). The G9a methyltransferase inhibitor, The same flow chemistry system equipped with a BRD4770, is expected to decrease H3K9 and high temperature tube reactor and a UV-150 H3K27 methylation and have no effect on HOXA9 photochemical reactor was used to perform two-step expression, but shows global decreases in flow photocyclization reactions, starting from 2- acetyllysine (41.2±9.2% reduction) and chlorobenzoyl chlorides and anilines. The residence monomethyllysine (16.1±5.9% reduction), increases time for the two-step reaction was 100 minutes in dimethyllysine (11.5±6.1% increase) and including 50 minutes for amide formation and 50 trimethyllysine (37.1±8.4% increase) and substantial minutes for photocyclization. The products were increases in total arginine methylation (90.2±13.9% separated by CombiFlash® RF and the purity was increase). As expected, both inhibitors of DOT1L, measured by HPLC. EPZ5676 and EPZ4777, inhibit HOXA9 expression Result: We have obtained a series of in mixed lineage leukemia cell line MOLM13 by phenanthridinones with different substituents. The qPCR (74.3±0.8% and 38.1±5.3%) reduction yields of most single-step flow photocyclization respectively). Unexpectedly, BRD4770 also reactions were 67% ~ 99%. The yields of two-step inhibited the expression of HOXA9 (47.9±1.2% flow photocyclization reactions were 47% ~ 77%. reduction). The purities of phenanthridinones were greater than Conclusion: These results demonstrate that HKMT 95%. The reactions can be scaled up without inhibition can result in unpredictable changes in changing reaction conditions, while the yields meet histone modifications that lead to unpredictable the requirements for industrial processes. changes in gene expression. Conclusion: We have developed a highly efficient, robust and environmentally-friendly method to prepare phenanthridinones and its analogues, which 42. Synthesis of Poly(ADP-ribose) Polymerase will be applied to the development of (PARP) Inhibitors (Phenanthridinones): The phenanthridinone-type PARP inhibitors and further Application of Flow Chemistry Techniques in our drug discovery efforts. Medicinal Chemistry Programs

Yuhua Fang and Geoffrey Tranmer. College of Pharmacy, University of Manitoba, Winnipeg, Manitoba, Canada

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43. Testicular Cytochrome P450 (CYP) Enzyme 44. In Vitro Bioactivation of Cyclic Phenol Expression Suppression by Phytoestrogen in Phosphate Analogues as Potential Inhibitors Adult Male Rats of Autotaxin

Haeun Chung1, A. Wayne Vogl2, Stelvio M. Kholud Algabbass, Sarah Petriew, Kevin Allen and Bandiera1 Ed Krol. 1Faculty of Pharmaceutical Sciences, 2Faculty of College of Pharmacy and Nutrition, University of Medicine, The University of British Columbia, Saskatchewan, Saskatoon, Saskatchewan, Canada Vancouver, British Columbia, Canada Purpose: Autotaxin (ATX) is a member of the Purpose: Genistein, a phytoestrogen and isoflavone, nucleotide pyrophosphatase/phosphodiesterase produces many biological effects in mammalian family of ectoenzymes. ATX has lysophospholipase cells, including inhibition of tyrosine kinase and D activity that catalyzes the hydrolysis of topoisomerase II and antioxidant activity. In lysophosphatidylcholine (LPC) into humans, the major route of exposure is through lysophosphatidic acid (LPA) and choline. LPA is a consumption of soy beans and soy-based food bioactive lipid mediator, which mediates many products. The aim of this study was to investigate on physiological and pathological processes including, the effect of genistein on the testicular CYP enzyme cell survival, proliferation, and migration. This expression levels. ATX/LPA signalling has been involved in a number Method: Adult male Sprague-Dawley rats were of human diseases including cancer. Because most randomized into five treatment groups with 6 rats LPA is produced by ATX activity, an inhibitor of per group. Rats received daily subcutaneous ATX would block subsequent LPA signalling. injections of genistein at 4, 40 or 400 µmol/kg, or Therefore ATX has become an attractive drug target estradiol benzoate at 0.4 µmol/kg, or vehicle at 1 for developing new anti-cancer therapies. Our ml/kg, for 2 weeks. One day after the last treatment, objective is to prepare and assess a series of novel rats were killed and their liver and testes were cyclic phenol phosphate analogues for their ability to immediately excised. Testicular microsomes were function as irreversible ATX inhibitors in vitro. prepared from individual rats and expression of Methods: Here we report (i) The development of CYP1B1, CYP2A1, CYP17A1, microsomal epoxide synthetic methodologies for the preparation of a hydrolase (mEH), CYP oxidoreductase (POR) and series of cyclic phenol phosphate analogues as 3β-hydroxysteroid dehydrogenase (HSD3β) was potential inhibitors of ATX; (ii) An assessment of analyzed by immunoblots. 5 µm-thick cryosections the aqueous stability of these analogues over 6h in of testis were prepared for immunohistochemical 50 mM TRIS buffer at 37°C and pH 8.0 and analysis analysis and its morphology was examined. by high performance liquid chromatography (HPLC) Result: Testicular protein levels of CYP2A1 and with UV detection; (iii) Determination of the ability mEH were decreased by 72% and 54%, respectively, of these compounds to inactivate ATX in vitro. This for rats treated with genistein at the highest dosage, will be performed by ATX inhibition assays, which and by 93% and 74%, respectively, for rats treated will be carried out by our colleagues at the with estradiol benzoate compared with the vehicle- University of Memphis. treated group. Similarly, treatment with genistein or Results: We successfully synthesized two model estradiol decreased testicular CYP17A1 and POR analogues A1 and A2 through a multi-step synthetic expression. Estradiol or genistein treatment did not procedure. Both compounds were determined to be change protein levels of HSD3β. No morphological stable at pH 8.0 and 37°C over 6 h. changes in testicular tissue were seen regardless of Conclusion: The proposed cyclic phenol phosphates treatment group. have not been previously prepared and can thus Conclusion: These findings indicate that genistein represent a new orientation for the development of at high doses can suppress testicular CYP enzyme new anti cancer therapies. expression in adult male rats. *Part of this work has been presented at Society of Toxicology Annual Meeting on March 15th in the form of a poster presentation.

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Pharmacokinetics & and was concentration dependent. THC demonstrated concentration dependent inhibition of Pharmacodynamics CYP3A4 and lipoxygenase and cyclooxygenase inhibition whereas this dual activity was not present in curcumin and calebin A. THC did not inhibit HDAC while this activity was demonstrated for 45. Tetrahydrocurcumin: Pharmacology and other curcumins. Bioavialability and Differential Conclusions: A sensitive, accurate and reproducible Pharmacological Effects of Curcumin analytical method was developed and employed to Anologues characterize the pharmacokinetic profile of THC. An unoptimised formulation of THC showed limited Júlia T. Novaes1, Ryan Lillico1, Casey L. Sayre2,1, 3 3 oral bioavailability but was detectable in serum and Kalyanam Nagabushnam , Muhammed Majeed , urine as glucuronides. THC exhibited a variety of Yufei Chen2, Emmanuel Ho1, Ted Lakowski1 Samaa 1 1 pharmacological activities. Alrushaid , and Neal M. Davies 1College of Pharmacy, University of Manitoba, Winnipeg, Manitoba, Canada; 2College of 46. Toxicity and Mechanisms of Transport of a Pharmacy, Roseman University of Health Sciences, Novel Organometallic Au(III) Compound South Jordan, Utah; 3Sabinsa Corporation, East Compared to Cisplatin on Rat Kidney Tissue Windsor NJ Slices ex vivo

Purpose: To develop a bioanalytical assay to Sarah Spreckelmeyera, c, Geny Groothuisa, Margot quantify THC, to characterize its bioavailability in van der Zeea, Stefan Stürupb, Chris Orvigc, Angela rats after (PO) administration, and to identify its Casinid pharmacological activities compared to other aDept. of Pharmacokinetics, Toxicology and curcumin analogues. Targeting, Groningen Research Institute of Methods: An isocratic UHPLC/MS/MS method was Pharmacy, University of Groningen, Antonius developed using a Waters Acquity UPLC BEH C18 Deusinglaan Groningen (The Netherlands); bDept. of column at a flow rate of 0.4ml/min. THC and the Pharmacy, University of Copenhagen, internal standard (curcumin) was monitored in Universitetsparken Copenhagen (Denmark); cDept. MRM positive mode at m/z 373.3>137.1 and m/z of Chemistry, The University of British Columbia, 369.3>177.1, respectively. The mobile phase was Vancouver, British Columbia, Canada; dSchool of 45% aqueous acetonitrile in 0.1% formic acid. For Chemistry, Cardiff University, Cardiff, UK the pharmacokinetic study THC was administered by oral gavage to male CD (Sprague-Dawley) rats (500 Purpose: The Pt(II) compound cisplatin is widely mg/kg) (n=3). Serum and urine samples were used as chemotherapeutic agent in cancer treatment. collected up to 72 h post-dose. In vitro anti-oxidant Unfortunately, there is still a lack of knowledge activity, Histone deactylase activity (HDAC), about its mechanisms of accumulation in vitro and histone acetyltransferase (HAT), anti-inflammatory ex vivo. So far, the organic cation transporter 2 activity (cyclooxygenase and lipoxygenase (OCT2) and copper transporter 1 (CTR1) are inhibition), and cytochrome P450 inhibitory assumed to be involved in the accumulation of activities of THC were examined using commercial anticancer platinum drugs. We recently reported on a assay kits. In vitro cell viability, and immune new series of gold(III)cyclometallated compounds, activation markers of cytokine / chemokine among which the most active in cancer cells was production were examined by enzyme-linked compound [Au(pyb-H)L1L2]n+ (pyb-H = C^N immunosorbent assays (ELISA) in SupT1 cells. cyclometallated 2-benzylpyridine, L1 = 1,3,5 Results: THC was poorly absorbed orally and was triazaphosphaadamantane, L2 = chlorido) (Figure 1). detected in serum and urine exclusively as The aim of this study is to evaluate the toxicity and glucoroconjugates in a 2:1 keto:enol ratio. THC the mechanisms of transport of cisplatin and exhibited multiple pharmacological effects in in gold(III) complex. vitro activity screens when compared to curcumin and another analogue (Calebin A). Anti-oxidant activity was as potent as curcumin and Calebin A

From Drug Discovery to Health Outcomes: Population to Patient | 87s

activity in several in vitro assays with relevant roles Cl NH3 in colon cancer, and diabetes etiology and PF6 Pt pathophysiology. N Au Cl NH Methods: Racemic liquiritigenin was intravenously 3 Cl P N (20 mg/kg) (n=4) and orally (50 mg/kg) (n=4) N administered to male Sprague-Dawley rats. N Concentrations in serum and urine were collected up Figure 1: Cisplatin and Au(III) compound to 72 hours after dosing and characterized via stereospecific HPLC. Pure enantiomeric forms were Methods: The mechanisms of accumulation of a tested to identify the stereospecific contribution to of cytotoxic cyclometallated gold(III) compound α-alpha-amylase activity in comparison to the compared to cisplatin are studied on an ex vivo racemate. In-vitro anti-oxidant, anti-cancer, anti- model of precision cut kidney slices (PCKS). The inflammatory activity (cyclooxygenase inhibition), main focus is the evaluation of the effect of and cytochrome P450 (CYP450) inhibitory activities cimetidine, an inhibitor for OCT2, on metal of liquiritigenin were examined using commercial compound treated rat kidney slices. Viability was assay kits. assessed by measuring ATP per protein content. Results: A short half-life (0.25-0.43 h) in serum was Metal content was evaluated using ICP-MS. Each observed, while a longer estimation of half-life (26- experiment was performed in triplicates for each 77 h) was observed using urinary data. The condition. flavonoid is predominantly excreted via non-renal Results: Our results show a correlation between the routes (fe values of 0.16-25%), and undergoes rapid viability of treated kidney samples and the metal and extensive phase II metabolism. Racemic content measured by ICP-MS in differents sets of liquiritigenin demonstrated a dose-dependent experiments (incubation times, temperature inhibition of α-amylase enzyme compared to its pure dependency and +/- OCT2 inhibitor). Moreover, we enantiomers which revealed more potent inhibitory confirmed the influence of OCT2 on cisplatin activities. Racemic liquiritigenin showed moderate accumulation, whereas Au(III)compound showed anti-proliferative activity on a HT-29 (human opposite effects. colorectal adenocarcinoma) cancer cell line that was Conclusion: Overall, the ex vivo model of PCKS dose-dependent and potent inhibitory effects on the represents a valuable further methodological cyclooxygenase-2 enzyme. The flavonoid did not development in the biological evaluation of inhibit the activity of cytochrome CYP 2D6 over the metallodrugs. concentration range studied but was a potent antioxidant. Conclusion: Stereoselective pharmacokinetics of 47. Pre-clinical Pharmacokinetic and liquiritgenin were demonstrated and the importance Pharmacological Characterization of of examining stereospecificity in the Liquiritigenin, a Chiral Flavonoid pharmacological effects of liquiritigenin was determined. Samaa Alrushaid1, Casey L. Sayre1,2, Stephanie E. Martinez1, and Neal M. Davies1 1College of Pharmacy, Faculty of Health 48. Effect of Isoproterenol on Catabolism of Sciences,University of Manitoba, Winnipeg, MB, Adenosine and Adenosine 5-‘triphosphate in Canada; 2College of Pharmacy, Roseman University Systemic Blood in vivo of Health Sciences, South Jordan, Utah Pollen K. Yeung, Shyam Sundar Kolathuru, Sarah Purpose: Liquiritigenin is a chiral flavonoid present Gallant and Remigius U. Agu in plant based food, nutraceuticals, and traditional College of Pharmacy and Department of Medicine, medicines. It is also an important ingredient present Faculties of Health Professions and Medicine, in licorice. The purpose of this study is to Dalhousie University, Halifax, NS, Canada characterize for the first time the stereoselective pharmacokinetics of liquiritigenin after oral and Purpose: Previous studies have shown that intravenous administration and its pharmacological metabolism of adenosine 5’-triphosphate (ATP) in red blood cell (RBC) may be a key factor

88s | CSPS/CC-CRS Conference 2016, Vancouver, BC, Canada

maintaining cardiovascular homeostasis. The study up to 80% of children with Dravet’s Syndrome investigates the effect of cardiovascular injury on treated with LTG had seizures worsen, manifesting adenosine and ATP catabolism in systemic blood new seizure types not attributable to disease but using a previously described freely moving rat characteristic of LTG overdose toxicity. The sole model in vivo. pathway of LTG metabolism and clearance is Method: The study was approved by the Dalhousie glucuronidation, specifically UDP-glucuronosyl University Committee on Laboratory Animals transferases (UGT) 1A4 and 2B7. Since drug (UCLA). After acclimatized to the experimental clearance by these isoforms does not mature for environment, Sprague Dawley (SD) rats were each years after birth, we hypothesized that the given either isoproterenol (30 mg/kg) or saline (1 mechanism of LTG toxicity in children is inadequate mL/kg) by subcutaneous (sc) injection. Blood glucuronidation. samples were collected sequentially for up to 6 hours Method: Glucuronidation of LTG was measured for measurement of red blood cell (RBC) using UHPLC-MS/MS in 91 livers (fetal 2, children concentrations of adenine nucleotides and plasma 46, adults 41, elderly 5) with the specific inhibitors concentrations of adenosine and its oxypurine hecogenin and AZT used to determine UGT1A4 and metabolites. UGT2B7 relative contribution to total LTG Results: We have found isoproterenol induced 50% glucuronidation. Protein expression was measured mortality under the experimental condition. Plasma by Western blot. concentrations of adenosine (ADO) and uric acid Results: The formation of LTG-2-glucuronide (UA) and red blood cell (RBC) concentrations of (LTG2G) was 0.433±0.025 nmol LTG2G/min/mg adenosine 5’-diphosphate (ADP) and adenosine 5’- (mean±SEM) and activity was lower in children monophosphate (AMP) in RBC were significantly (0.34±0.04) compared with adults (0.49±0.03) but higher in the isoproterenol treated rats (p < 0.05 for not significantly (p=0.09). Total activity was all the comparison). On the other hand, plasma 0.330±0.02 and 0.080±0.006 in the presence of AZT concentrations of hypoxanthine (HYP) were higher and hecogenin, respectively, suggesting UGT1A4 in the control group (p < 0.05), but there was no accounts for 80% of metabolic clearance and statistically significant changes in ATP UGT2B7 20%. Both UGT isoforms protein concentrations in the RBC (p > 0.05). correlated with total activity (r=0.40 and 0.42 Conclusion: Cardiovascular injury induced by p<0.0001). The average UGT1A4 protein isoproterenol resulted in breakdown of ATP to ADP expression did not vary significantly but children and AMP in the RBC and also breakdown of ADO had greatest range (14-fold) compared with adults to UA in plasma and other tissues (supported in part (4.7-fold) and the elderly (1.3-fold). The UGT2B7 by Dalhousie Faculty of Health Professions protein levels for children, adults and the elderly Research Development Grant and Pharmacy were 0.73±0.04, 0.75±0.04 and 1.11±0.09, Endowment Foundation). respectively. The elderly had significantly higher UGT2B7 expression than children (Dunn’s, p<0.01) and adults (Dunn’s, p<0.05), with children having 49. Lamotrigine Metabolism by UDP- greatest variability (19-fold) as compared with adults Glucuronosyltransferases, UGT1A4 and (6.3-fold) and the elderly (1.6-fold). Protein levels of UGT2B7, and their Role in Pediatric Toxicity UGT1A4 and UGT2B7 were significantly correlated Through Inadequate Glucuronidation (r=0.34, p<0.01, Pearson). Conclusion: These data confirm UGT1A4 and Zoe Riches, András Szeitz, Tara L. Klassen and UGT2B7 are involved in LTG metabolism and that Abby C. Collier. developmentally lower and more variable expression Faculty of Pharmaceutical Sciences, The University likely causes LTG toxicity in children. of British Columbia, Vancouver, Canada.

Purpose: Lamotrigine (LTG) could be useful in childhood epilepsy. However, reports suggest that

From Drug Discovery to Health Outcomes: Population to Patient | 89s

AFPC POSTER PRESENTATIONS - JUNE 1, 2016

POSTER AUTHOR NAMES ABSTRACT TITLE NUMBER AFPC - 1 Waseem M. Abu-Ashour, Laurie K. Diabetes and the Occurrence of Infection in Primary Twells, James E. Valcour, John-Michael Care: A Matched Cohort Study Gamble AFPC - 2 Naif Aljuhani, Lindsey Spryut, Randy The Oxidation of the Anticancer Drug Metabolite, 6- Whittal, Arno Siraki Mercaptopurine Ameliorates Cu-Zn Superoxide Dismustase Activity: Potential Involvement of Peroxymonocarbonate AFPC - 3 Renée Dagenais, Arden R. Barry, Mary The Bus Analogy: A New Analogy to Help Pharmacy H. H. Ensom Students Conceptualize the Well-Stirred Model AFPC - 4 Jam Bravo, Mirando So, Karen J. Descriptive Analysis of Fourth Year Pharmacy Cameron, Cindy Natsheh, Gordon A. Students' Perspective on Virtual Interactive Case (VIC) Tait Software AFPC - 5 Rene Breault, Jill Hall, Sheila Walter, Experiential Education in the PharmD for Practicing Ken Cor Pharmacists Program: Preceptor Experiences and Expectations AFPC - 6 Rene R. Breault, Christine A. Hughes, Compensation Plan for Pharmacy Services: Deborah Hicks, Theresa J. Schindel Communicating Change in Alberta AFPC - 7 Dion R. Brocks, Ken Cor The Relationship Between Grades in Prerequisite Pharmacy Courses and Pharmacy Grades at the University of Alberta AFPC - 8 Divna Calic, Ryan G. Lillico, Ted M. Significant Changes in Cefazolin Protein Binding Lakowski, Casey Sayre, Sheryl A. During Cardiac Surgery with Cardiopulmonary Bypass Zelenitsky AFPC - 9 Karen J. Cameron, Salma Satchu, Jenny Assessment of PharmD Student Performance on Chiu, Anna Chiu, Dhwani Raiyani, Eric Standardized Medication Reconciliation Validation at Luloff, Andrea J. Cameron, Olavo Academic Hospitals Fernandes AFPC - 10 Fong Chan, Katherine Seto Implementation of an Assessment Strategy Using Human Patient Simulation Technology to Evaluate Pharmacy Students AFPC - 11 Theresa L. Charrois, Jay Mutch, Defining Characteristics of Successful Pharmacists: A Lydia Cheung, Jill J. Hall, Meagen M. Qualitative Study Rosenthal, M. Ken Cor AFPC - 12 Gilles Leclerc, Marie-Lou Deschamps, eHealth Education: Anatomy of an Interprofessional Antoine Lebrun, Michael Cardinal, Initiative Mathieu Nobert, Charles-Edouard Morel, Christiane Nathalie Geillon AFPC - 13 Justin Mak, Doret Cheng, Cindy Entrustable Professional Activities (EPAs) for Natsheh Pharmacy? A Literature Review AFPC - 14 Jenny Chiu, Monica Lee Comparison of Pharmacy Students' and Pharmacists' Activities using a Clinical Pharmacist Workload Measurement Tool AFPC - 15 Anna Cieślak, Jocelyn Trottier, Melanie Docosahexaenoic Acid Activates Bile Acid Verreault, Frederic Calon, Marie-Claude Detoxification in Mice Vohl, Piotr Milkiewicz, Olivier Barbier

90s | CSPS/CC-CRS Conference 2016, Vancouver, BC, Canada

AFPC - 16 Chesarahmia Dojo Soeandy, Faraz Defining an Alternative Murine Model of Cerebral Salmasi, Jeffrey Henderson Ischemia: Focal Vasoconstriction via Endothelin-1 AFPC - 17 Nyasha Gondora, Michael A. Beazely, Chronic Early Life Social Isolation Affects Expression John G. Mielke of TrkB and NMDA Receptor Proteins in a Sex- Specific Manner AFPC - 18 Kerry B. Goralski, Steven R. Hall, Jay Jadomycins induce DNA Damage and Caspase- Toulany, David L. Jakeman dependent Apoptosis in Human MDA-MB-231 Breast Cancer Cells AFPC - 19 Arun K. Verma, Judith Soon, John Y. The Interprofessional Medication Reconciliation Groumoutis Program: A Quantitative Evaluation AFPC - 20 Arun K. Verma, Judith A. Soon, Jackson The Interprofessional Medication Reconciliation Stewart Program: A Qualitative Analysis AFPC - 21 Jill J. Hall, Rene R. Breault, Sharon A Model of Innovative Integration in the Doctor of Marsh, Candace M. Necyk, Theresa J. Pharmacy for Practicing Pharmacists Program Schindel AFPC - 22 Michael B. Weale, Jennifer E. Isenor, Advancing and Evaluating the Drug Information Melissa Helwig, Susan K. Bowles Resources (DIR) Website AFPC - 23 Derek J. Jorgenson, Eric J.L. Landry, A Mixed Methods Evaluation of a Medication Katherine J. Lysak Assessment Clinic Located Within a Pharmacy School AFPC - 24 Deborah V. Kelly, A. Nicole Pittman Development of a Pharmacist-run Medication Therapy Services Clinic AFPC - 25 Alexander D. Smith, Arnab Ray, Tara Classic Labs for a New Program: Development of Klassen Integrated Pathophysiology Activities for the Entry-to- Practice PharmD Curriculum AFPC - 26 Alexander D. Smith, Arnab Ray, Tara L. Bandana Science: Peers in the Preparation for and Klassen Teaching of Pathophysiology in PharmD Entry to Practice Integrated Activities AFPC - 27 Mia G. Losier, Megan E. Harrison, Point Prevalence Survey of Antimicrobial use at the Emily K. Black, Heather L. Neville, B. Queen Elizabeth II Health Sciences Centre in Halifax, Lynn Johnston, Kim A. Abbass, Kathryn Nova Scotia L. Slayter, Ingrid S. Sketris AFPC - 28 Melissa Lu, Brenna Shearer, Alberto Survey of Knowledge and Attitude Regarding HPV Severini, Silvia Alessi-Severini Infection, Vaccine and Testing AFPC - 29 Katherine J. Lysak, Shawna L. Pharmacy Student Perceptions of a Medication Berenbaum, Stephanie M. Mulhall, Assessment Clinic Located Within a Pharmacy School Jason P. Perepelkin, Yvonne M. Shevchuk, Jeff G. Taylor, Derek J. Jorgenson AFPC - 30 Pedram Rafiei, Azita Haddadi Docetaxel Loaded PLGA Nanoparticles for Intravenous Application: Pharmacokinetics and Bio- distribution profile AFPC - 31 Annie-Claude Couture, Sarah Girard, An Observational Study to Assess the Accuracy of Marc-André Renaud, Marie Vincent- Carboplatin Area under the Concentration-time Curve Tremblay, Jean-Luc Dionne, Robert in Oncology Patients with Standardized Creatinine Bell, Michel Vallée, Robert Robitaille, Measurement and Modern Formulas for Renal France Varin, Philippe Bouchard Function Estimation AFPC - 32 Miao Yan (Marilyn) Sun, Tara Leah Novel Missense Mutations in SCN1B as a Cause of Klassen Pediatric Epilepsy

From Drug Discovery to Health Outcomes: Population to Patient | 91s

Poster Session 2

CSPS and CC-CRS Posters

AFPC Posters

Thursday, June 2

92s | CSPS/CC-CRS Conference 2016, Vancouver, BC, Canada

Posters - Session 2

Thursday, June 2

This could contribute to the increased risk for Biomedical Sciences cardiovascular disease associated with both types of diabetes. Reference: Pilote S, Gélinas C, Patoine D, Drolet B, Simard C. Altered cardiac protein expression of 50. Altered Cardiac Protein Expression of CYP2j CYP2J2 in mouse models of Type I and Type II in Mouse Models of Type I and Type II diabetes. American Society for Clinical Diabetes Pharmacology and Therapeutics 117th Annual Meeting. Clin Pharmacol Ther 2016;99 (Suppl C. Gélinas1, S. Pilote2, D. Patoine2, B. Drolet1,2, C. 1):S47. Simard1,2; Acknowledgement: Carolanne Gélinas is the 1Faculté de Pharmacie, Université Laval, Québec, recipient of 2016 GSK/CSPS National Québec, 2CRIUCPQ, Québec, Québec, Canada Undergraduate Student Research Program Award.

Purpose: Arachidonic acid (AA) is metabolized by cytochromes P450 (CYP450) in different products 51. Determining the Kinetic Parameters of such as epoxyeicosatrienoic acids (EETs) and 20- SET7/9 Protein Lysine Methyltransferase hydroxyeicosatetraeonic acid (20-HETE) known to have cardioprotective and cardiotoxic effects, Nicholas Stesco, Ryan Lillico, and Ted M. respectively. Studies showed that Type I (T1D) and Lakowski. Type II (T2D) diabetes can alter the delicate balance College of Pharmacy, University of Manitoba, between synthesis of EETs and 20-HETE by Winnipeg, Manitoba, Canada modulating protein expression of different cytochromes such as CYP4A, CYP4F and CYP2C. Purpose: Histone lysine methylation is an CYP4A and CYP4F metabolize AA in cardiotoxic epigenetic mechanism which can modulate gene 20-HETE and studies showed that expression is up- expression and has been implicated in the various regulated in both types of diabetes. In contrast, forms of cancer. The majority of enzymes CYP2C metabolizes AA in EETs, which are down- responsible for catalyzing lysine methylation are regulated in T1D and T2D. within a family of enzymes containing a SET Aim: To determine if T1D and T2D could also domain. The aim of this study is to determine the modulate the cardiac protein expression of CYP2j. kinetic parameters of the lysine methyltransferase Method: Mouse models of T1D (streptozotocin) and SET7/9 using liquid-chromatography and tandem T2D (C57BLKS/J-db/db) were used in this study. mass spectrometry (LC-MS/MS) techniques. After sacrifice, ventricles were collected, washed in Methods: Reactions are carried out in vitro using cold PBS and snap frozen. Total proteins were SET7/9 enzyme (New England Biolabs), S- extracted using ice-cold lysis buffer. Western blots adenosyl-L-methionine (Cayman Chemical), and a were performed to assess CYP2j protein expression. peptide based on the first 21 amino acids of the Results: We obtained a significant decrease of histone H3 protein (Epigentek). After 1 hour murine protein expression of cardiac CYP2j in T1D incubation at 37°C, reactions are heat killed at 75°C group (0.5720 ±0.0328) and in T2D group for 5 min. Samples are then taken and prepared for (0.8029±0.0325) in comparison to control group LC-MS/MS analysis. Analysis is performed using (1.0460±0.0619). two separate assays, one to quantify histone Conclusion: This study showed that protein modifications and one to quantify S-adenosyl-L- expression of CYP2j is decreased in both T1D and homocysteine (SAH), a co-product of the T2D. This modulation could disrupt the delicate methylation reaction. The SAH production data are balance between EETs and 20-HETE synthesis by then used to calculate the kinetic parameters of the pushing the balance towards the cardiotoxic side. reaction, KM and VMax (SigmaPlot).

From Drug Discovery to Health Outcomes: Population to Patient | 93s

Results: The KM for S-adenosyl methionine was dependent manner if compared to untreated disease determined from SAH data to be 0.48 +/- 0.07 mice (P<0.05). Only 24g/kg EG significantly pmol/min, the Vmax for the reaction was 0.26 +/- influenced XOD activity in the liver (P<0.05). 0.008 µM. The data from the histone modification Conclusion: The research demonstrates that assay gave a KM of 0.22 +/- 0.03 µM and a Vmax of aqueous extracts of EG had reducing effects on uric 0.19 +/- 0.004 pmol/min. acid. EG might be used as a novel anti- Conclusion: The discrepancy between the values hyperuricemia agent. reported from each assay may indicate that SET7/9 Acknowledgement: The authors acknowledge can automethylate. Automethylation has been shown Scientific Grant of Jiangxi Province, China (No. to alter or halt the activity of other 20144BDH80005 and 20151BBB70268) for methyltransferases, so this has implications for financial support. SET7/9. It is also of note that the histone modification assay showed that SET7/9 only UA liver XOD Group Dose catalyzed formation of monomethyllysine, making (umol/L) (U/gprot) this the first time that this has been confirmed with Normal 152.80 ± 25.07 ** 6.92±0.31 Untreated 450mg/kg such sensitive methods. 322.01 ± 35.08 7.57±1.13 disease Positive 10mg/kg 190.45 ± 43.14 ** 6.58±0.74 52. Hypouricemic Effects of Aqueous Extract of control Erding Granules in Potassium Oxonate- Erding 24g／kg 185.82 ± 43.37 ** 6.17±0.84* Induced Hyperuricemic Mice Erding 12g／kg 174.75 ± 43.16 ** 7.02±0.73 264.58 ± Erding 6g／kg 7.32±0.88 Jieyu Zuo1, Hui Jian2, Zhengyun Zuo2, Shilin Yang2 79.01*## and Raimar Loebenberg1. * compared with untreated group, * P<0.05, ** P< 0.01 1Faculty of Pharmacy and Pharmaceutical Science, # compared with Erding (12g/kg) group, # P< 0.05, ## P< 0.01 University of Alberta, Edmonton, Alberta, Canada;

2Jiangxi University of Traditional Chinese Medicine 53. Compatibility Effects of Herb Composition in Erding Granules (GR) is a Traditional Chinese Reducing Uric Acid Level in Hyperuricemic Medicine (TCM) preparation generally used for heat Mice clearing and detoxifying listed in the Chinese Pharmacopeia (ChP). According to TCM of the Jieyu Zuo1, Hui Jian2, Zhengyun Zuo2, Shilin Yang2 formula might have anti-hyperuricemic properties. and Raimar Loebenberg1. Purpose: The study aimed to evaluate the effects of 1Faculty of Pharmacy and Pharmaceutical Science, aqueous extract of Erding Granules (EG) on University of Alberta, Edmonton, Alberta, Canada; reducing serum levels of uric acid (SUA) in 2Jiangxi University of Traditional Chinese Medicine potassium oxonate-induced hyperuricemia mice. The extract’s potency to inhibit uric acid production was Introduction: Herb compatibility is one of the key assessed. characteristics of Traditional Chinese Medicine Method: An aqueous extract of EG following the (TCM). Rather than monotherapy, TCM frequently ChP procedure was made. The extract was uses multi-herb formulas to exert therapeutic action intragastrically administered to mice for 5 and modulate pharmacological effects. consecutive days. The hyperuricemia animal model Purpose: The study aimed to evaluate the anti- was induced by potassium oxonate (PO) 1h before hyperuricemic effects between aqueous extracts of the last administration of the extract. Blood samples Erding Granules (EG) and aqueous extracts of the were taken 2h after PO injection and examined SUA corresponding individual herbs. and xanthine oxidase (XOD) activity in liver in 6 Method: Erding formula is composed by whole groups of male Kunming Mice (n=10 each), normal, plant extracts of Viola yedoensis Makino (Viola), untreated disease, positive control and three different Taraxacum mongolicum Hand.-Mazz.(Taraxacum), doses (24g/kg, 12g/kg and 6g/kg) of the aqueous Lobelia chinensis Lour.(Lobelia) and root extract of extracts were evaluated. Isatis indigotica Fort. (Isatidis). We extracted each Results: Each group of aqueous extract of EG plant extract following the EG preparation protocol showed significantly reduced SUA but not in a dose

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listed in the Chinese Pharmacopeia. The extracts concentration, both S1P receptors 1 and 2 (S1PR1 were intragastrically administered to mice for 5 and S1PR2), which are the main S1P receptors in consecutive days. The hyperuricemia animal model breast cancer, were expected to be blocked. S1P was induced by potassium oxonate (PO) 1h before would accumulate inside the cells and induce the last dose. Blood sample were collected 2h after apoptosis via its intracellular functions. However, PO injection and serum uric acid (SUA) was little is known about the in vivo or in vitro examined in 8 groups of male Kunming Mice (n=10 degradation speed of S1P; and thus, we investigated each), normal, untreated disease, positive control, whether using S1PR1 antibody could prevent cancer Erding, Viola, Taraxacum, Isatidis and Lobelia. cell proliferation and survival through S1PR1 Results: Each group of aqueous extract showed signaling due to reduced S1P concentration caused significantly reduced SUA (Erding, viola, by degradation. taraxacum, Isatidis, and lobelia: 139.11±32.85, Method: We use CellToxTM Green Cytotoxicity 156.78±25.56, 186.59±73.55, 217.89±49.51, and Assay Kit to test the cytotoxicity effect of S1PR1 234.48±26.16) as compared with untreated disease antibody alone over a wide range of concentration as mice ( 285.94±26.67, P<0.01). The Erding extract well in combination with 0.1 µM, 1 µM and 10 µM worked better in reducing uric acid levels, especially S1P against breast cancer cell lines MCF7, SK-BR-3 compared with Isatidis and Lobelia (P<0.01). and MDA-MB-231. Conclusion: Combinations of two or more herbs can Results: No toxicity of S1PR1 antibody was be more effective in reducing uric acid level than observed against MCF7 and SK-BR-3 cells; using single herb extracts only. however, it caused ~10% cytotoxicity towards the Acknowledgement: The authors acknowledge MDA-MB-231 cells at 18 ng/mL after 48 h of Scientific Grant of Jiangxi Province, China (No. treatment. The combination of S1P and S1PR1 20144BDH80005 and 20151BBB70268) for antibody exhibited ~24% cytotoxicity at 0.1 µM S1P financial support. and 32 ng/mL S1PR1 antibody towards the SK-BR- 3 cells. Group Dose (g raw UA（umol/L) Conclusion: S1PR1 antibody alone could elude low material/kg) cytotoxicity effect against human breast cancer Normal 142.80±51.52＊＊ depending on the cell type, antibody concentration Untreated 450mg/kg 285.94±26.67 and treat time. Meanwhile, its combination with disease S1P could cause higher cytotoxic effects against the Positive 10mg/kg 135.72±15.14＊＊ breast cancer cells. control Erding 24 139.11±32.85＊＊ Viola 6 156.78±25.56＊＊ 55. Structural Modeling of Voltage-gated Sodium Taraxacum 6 186.59±73.55＊＊ Channels: Improving Molecular Diagnostics Isatidis 6 217.89±49.51＊＊## in Pediatric Epilepsies Lobelia 6 234.48±26.16＊＊## *compare with untreated group, * P<0.05, ** P<0.01 Alexander D. Smith, Tara L. Klassen. #compare with Erding group, # P<0.05, ## P<0.01 Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada

54. The Cytotoxic Effect of Sphingosine-1- Purpose: There are >600 published epilepsy- phosphate Towards Human Breast Cancer causing variants in SCN1A and SCN2A, the genes Cells in vitro encoding the voltage-gated sodium channels Nav1.1 and Nav1.2. Mutations in these gene cause severe Shujun Xiao and Jian Yang. epilepsy (Dravet/SMEI) as well as milder (GEFS+) College of Pharmacy and Nutrition, University of and age limited (BFNS) syndromes. The majority Saskatchewan, Saskatoon, Saskatchewan, Canada are not inherited, arising de novo in the patient, and have not been previously reported. There is little Purpose: Sphingosine-1-phosphate (S1P), a correlation between disease severity and genotype, bioactive sphingolipid metabolite, selectively drastically limiting the interpretation of current gene induced apoptosis in breast cancer cells at tests for informed clinical decision making. We concentration higher than 1 µM. At this hypothesize that syndrome severity can be predicted

From Drug Discovery to Health Outcomes: Population to Patient | 95s

from the relative energetics (Gibb’s Free Energy) of preference elicitation, we estimated respondents’ sodium channel destabilization during its transition relative preferences for 43 different possible from the closed to open state, resulting from the characteristics of fundraising campaigns aimed at missense amino acid substitution. supporting biomedical research. Respondents rated Methods: Homology models of the human Nav1.1 each characteristic based on its relative desirability and Nav1.2 were generated using Biovia Discovery and importance, and these ratings were used to Studio where bacterial voltage-gated sodium channel calculate preference scores ranging from 0 (low crystal structures in the open and closed preference) to 8 (high preference) for each conformations were used as templates. Personal characteristic. epilepsy mutations were introduced via in silico Results: Average preference scores indicate that mutagenesis and the energetic consequences were respondents had an overwhelming preference for ranked to quantify the structural perturbation of each donating to projects conducted by non-profit state. research organizations (mean=5.98, sd=2.96) instead Results: Stabilization and destabilization of both of for-profit companies (mean=1.14, sd=2.21); channel proteins was observed. This is highly projects that have the potential to yield a curative mutation dependent, but independent of subunit or therapy (mean=6.08, sd=3.34); projects that focus on ultimately the position within the protein – diseases with a high prevalence (1 in 15: mean=5.67, homologous and adjacent positions having different sd=3.17; 1 in 100,000: mean=1.51, sd=2.89); and energetic consequences. The bulk of mutations projects that focus on diseases with an early median impact stability, with most destabilizing channel age of onset (Age 5: mean=6.13, sd=2.92; Age 70: conformation. mean=0.82, sd=2.02) Conclusion: Current bioinformatics tools have Conclusions: Our results suggest that project-based limited use in interpreting SCN1A and SCN2A online fundraising has significant potential to serve mutations, such that new in silico tools to improve as a complementary source of research funding for risk prediction accuracy are urgently required. many drug development projects, and could help to Predictive structural modeling will allow refinement facilitate new business models for drug of molecular diagnostic interpretations, improving development. However, research projects focused on diagnosis, prognosis, and therapeutic decision rare or age-related diseases and those conducted by making for truly personalized medicine. biotechnology startups may have difficulty persuading donors to contribute financially.

56. Preferences for Donating Money to Support Drug Development Research Projects in a 57. FRET-labeled Self-assembled Nanoprobe for Sample of Canadian and U.S. Adults Rapid and Sensitive Detection of Postoperative Pancreatic Fistula Nick Dragojlovic and Larry D. Lynd. Faculty of Pharmaceutical Sciences, University of Nobuhito Hamano, Masaharu Murata, Takahito British Columbia, Vancouver, BC Kawano, Jing Shu Piao, Sayoko Narahara, Ryosuke Nakata, Tomohiko Akahoshi, Tetsuo Ikeda, Makoto Purpose: Biomedical researchers are increasingly Hashizume turning to project-based online fundraising (i.e. Department of Advanced Medical Initiatives, crowdfunding) as a complementary source of Faculty of Medical Sciences, Kyushu University, research funding. Researchers and organizations Higashi-ku, Fukuoka, Japan (e.g., universities, foundations, or biotech incubators) who seek to use this type of fundraising Purpose: Postoperative pancreatic fistula (POPF) is to finance both the pre-clinical and clinical stages of the most serious and challenging complication drug development research projects would benefit following gastroenterological surgery. Activated from being able to identify the types of projects that pancreatic juice leaking from the organ remnant are most likely to appeal to donors. contains proteases that attack the surrounding tissue, Methods: To help inform the fundraising strategies potentially leading to severe inflammation, tissue adopted by researchers, we conducted an online necrosis, and fistula formation. However, it is survey of Canadian (n=413) and U.S. (n=401) difficult to observe pancreatic leakage during adults. Using the self-explicated method (SEM) of surgery and to evaluate the protease activity of

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leaked fluid at the patient’s bedside. Therefore, we However, the nature of Ivacaftor’s interaction with have developed Heat Shock Protein (HSP) -based mutant CFTR is still under investigation. The aim of Förster resonance energy transfer (FRET) nanoprobe this study is to use photolabelling of Ivacaftor to able to detect the activated pancreatic juice through probe for the binding site on mutant CFTR. the pancreatic proteases in drainage fluid. Method: A limited SAR study showed retention of Method: A variety of HSP-FRET nanoprobes were the Ivacaftor potentiating activity with deletion of synthesized, and their reactivity with proteases was either of the t-Bu groups on 1. This lead to a compared by fluorescence spectra. Drainage fluid synthesis program to substitute the t-Bu groups for was obtained from 6 patients who underwent the photo-labelling diazirine motifs (2,3), to probe gastrectomy or distal pancreatectomy. The FRET for Ivacaftor’s binding site of on ΔF508 CFTR. protein nanoprobes [10 µM] were added to the Results: Synthetic efforts have led to significant drainage fluid [80% v/v], and the mixture was progress towards the synthesis of 3 monitored via real-time imaging using a digital Conclusion: The potentiating activity of the photo- camera relayed through a dichroic filter. labelled analogues 2, and 3 will be confirmed in Results: The HSP-FRET probe was constructed by functional assays before being tested in binding subunit exchange of each dye-labeled engineered studies with F508-del CFTR containing liposomes. HSP, resulting in a spherical nanocage of approximately 10 nm in diameter, which exhibited very high stability against degradation in blood plasma and no remarkable toxicity in mice. The efficiency of FRET was found to depend on both the dye orientation and the acceptor/donor ratio. Pancreatic proteases, including trypsin, α- chymotrypsin, and elastase, were quantitatively analyzed by fluorescence recovery with high 59. Expenditures Guided by the Concept of specificity using the HSP-FRET nanoprobe. Essential Medicines in Brazil: The Case of the Furthermore, the HSP-FRET nanoprobe was Fibrates sufficiently sensitive to detect POPF in the Rachel Magarinos-Torres 1, Paulo Eduardo Coutinho pancreatic juice of patients using only the naked eye 2 2 within 10 min. Marques , Claudia Garcia Serpa Osorio-de-Castro and Larry David Lynd 3. Conclusion: A novel nanoprobe has been developed 1 for the detection of POPF based on the FRET School of Pharmacy, Federal University of the State of Rio de Janeiro, Brazil; 2Oswaldo Cruz mechanism that can be visually identified during 3 gastroenterological surgery. Foundation, Ministry of Health, Brazil; Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, Canada 58. Using Photo-labelled Analogues of Ivacaftor to Probe for the Binding Site on Mutant Purpose: The concept of essential medicines is CFTR internationally recognized as a health strategy to rationalize the use of medicines. Brazil has had an C. Michael Hamilton1; Gang Chen1; Maurita Hung3; Essential Medicines Lists (EML) since 1964. In Krimo Toutah2; Robert Young1; Christine Bear3; 2012, the number of items in the Brazilian EML Russ Viirre2 (BN-EML) increased 54,4%. In that year 1Simon Fraser University, Department of Chemistry, ciprofibrate was included, although others fibrates Burnaby, BC; 2Ryerson University, Department of were already covered. The aim of this study was to Chemistry, Toronto, ON; 3Hospital for Sick analyze the trends of Brazilian Federal Government Children, Molecular Structure and Function, expenditures with ciprofibrate and fenofibrate Toronto, ON, Canada between 2008 and 2013. Method: Data were extracted from the Brazilian Purpose: The first approved Cystic Fibrosis (CF) Federal Government procurement database and the therapeutic Ivacaftor (1) was discovered through a four last editions of the BN-EML. The analysis high-throughput functional screen measuring considered all medicines purchased by the federal potentiation of the chloride channel CFTR. government, from January 2008 to December 2013.

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To measure expenditures, the total value of each of our research program is to design and synthesis of purchase was calculated by multiplying the unit potent inhibitors of androgen receptor BF3. price by the volume and this value was adjusted for Method: Previous work using in silico-guided inflation using the Extended National Consumer screening led to the discovery of 2-(indol-3-yl)- Price Index (IPCA). Cost was presented in Reais indoline 1 as potent BF3 inhibitor which showed (R$); 3 Reais = 1 Canadian dollars (CAD) (March excellent antiandrogen potency and anti-PSA 2016). activity as well as significant reduction of tumor Results: The expenditures with both medicines growth in prostate cancer xenografts. However, this increase over time. The Brazilian Federal series of compounds were found to be chemically Government expenditures with ciprofibrate from unstable owing to their ability to undergo 2008 to 2014 amount 240 thousand Reais. In the racemization under acidic conditions and the same period, the expenditures with fenofibrate were tendency to readily oxidize. Our synthetic efforts led 110 thousand Reais. The increase between 2011 and to the identification of a more stable, second series 2012 was higher for ciprofibrate than for fenofibrate. of BF3 inhibitors 2 featuring two heteroaryl moieties The government spent 27.392,11 Reais with connected in a flat spatial arrangement as the key ciprofibrate in 2011 and 75.879,27 Reais in 2012 structural requirement. (increase approximately of 177,0%). However, the Results: We applied this key structural feature to expenditures with fenofibrate increase 12,2% from generate the third series of BF3 inhibitors, the 2011 to 2012 (from 19.004,00 to 21.317,00). indolyl-quinoline series 3. In which, compound Conclusions: The Brazilian Federal Government VPC13566 was found to be effective in inhibiting spent more with ciprofibrate than with fenofibrate, AR-transcriptional activity in vitro in prostate cancer although the evidence of therapeutic benefits for the cell lines including an enzalutamide-resistant cell first one is lower and inconclusive. The inclusion of line. It also showed significant inhibition of tumor ciprofibrate on the NB-EML greatly increased the growth in prostate cancer xenografts. Results from expenditures of the Federal Government with this the structure activity and relationship of the indolyl- class of medicine. quinoline series and lead optimization process will be presented. Conclusion: Our results reinforce that targeting 60. Discovery of 2-(1H-Indol-3-yl)-quinolines as alternative sites other than the androgen binding site Novel Inhibitors of Androgen Receptor on the AR may help to circumvent the drug Binding Function 3 (BF3) resistance problem in prostate cancer treatment. The lead compounds identified from the indolyl- 1 1 Christophe Andre , Sankar Mohan , Ravi S.N. quinoline series has clinical potential for the 2 2 2 Munuganti , Nada Lallous , Eric Leblanc , treatment of drug-resistant forms of prostate cancer. 2 2 Mohamed D.H. Hassona , Shannon Awrey , Nader Al Nakouzi2, Helene Morin2, Mani Roshan-Moniri2, Kriti Singh2, Sam Lawn2, Takeshi Yamazaki2, Hans Adomat2, Mads Daugaard2, Emma Tomlinson Guns2, Paul S. Rennie2, Artem Cherkasov2, Robert N. Young*&1 1Department of Chemistry, Simon Fraser University, Burnaby, BC; 2Vancouver Prostate Centre,

University of British Columbia, Vancouver, BC, Canada 61. Novel Antimicrobials Derived from Parasitic Nematodes Purpose: Drug resistance is the major problem for the currently available antiandrogen prostate cancer Ankur Midha1, Jacob Lory1, Katharina Janek2, drugs, Bicalutamide, Flutamide, Nilutamide and Sebastian Günther3, Karsten Tedin3, Diego Serra4, Enzalutamide which target the androgen binding Regine Hengge4, Josephine Schlosser1, Susanne pocket of AR. A functional surface pocket of the Hartmann1 androgen receptor (AR) called binding function 3 1Freie Universität Berlin, Institute for Immunology; (BF3) has been studied extensively as an alternative 2Charité - Universitätsmedizin Berlin, Institute for target to overcome resistance mechanisms. The goal

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Biochemistry; 3Freie Universität Berlin, Institute for Clinical Sciences & Pharmacy Microbiology and Epizoonotics; 4Humboldt- Universität zu Berlin, Institute for Biology, Berlin, Practice Germany

Purpose: Increasing antibiotic resistance in pathogens resulting in less effective antibiotics poses 62. Co-prescription of Antipsychotic and a severe threat to human health, highlighting the Antiparkinson Medications: Adherence to urgency for the development of novel antimicrobial Guidelines and the STOPP (Screening Tool of agents. Antimicrobial peptides (AMPs) are an Older Persons’ Potentially Inappropriate ancient component of innate immunity, distributed Prescriptions) Criteria in Beneficiaries of the across all multicellular organisms, providing Nova Scotia Seniors’ Pharmacare Program protection against various pathogens. Parasitic Sara Rehan,1 Ingrid Sketris1, Barbara Hill-Taylor1, nematodes are widespread in nature, infecting 1,2 1 humans and animals alike. As nematodes induce Heather Rigby , Kara Thompson 1College of Pharmacy, Dalhousie University, Nova chronic infections that comprise tissue migrating life 2 stages without inciting overt inflammatory Scotia; Nova Scotia Health Authority, Nova Scotia responses, we hypothesize that intestinal nematodes release factors that interfere with the host mircobiota Purpose: To study the trends in co-prescription of and thus exhibit antimicrobial activities. The aim of antipsychotic and antiparkinson medications for our studies is to test excreted and secreted products older persons and determine adherence to guidelines (ESPs) from parasitic nematodes for antimicrobial and STOPP criteria. We had two hypotheses 1) the activity. number of potentially inappropriate prescriptions Methods: ESPs are collected from ex vivo cultured were frequent 2) the likelihood of potentially nematodes (A. suum, T. suis, H. polygyrus), inappropriate prescribing was associated with patient fractionated by adsorption chromatography and characteristics (age, sex) and year of prescription. methanol gradient elution, separated by gel Methods: We conducted a retrospective electrophoresis, and tested for antimicrobial activity. observational study and determined the dispensing Those fractions demonstrating antimicrobial activity of antipsychotic and antiparkinson medications for are then subjected to peptide sequencing by liquid beneficiaries of the NS Seniors’ Pharmacare chromatography-tandem mass spectrometry analysis. Program aged ≥ 66 years from April 1, 2009 to Results: Gel electrophoresis reveals numerous March 31, 2014. The STOPP criteria (D6) proteins and peptides recovered from ESPs. Radial recommends quetiapine and clozapine in those with diffusion assay with ES fractions demonstrate broad parkinsonism or Lewy Body Disease and considers antimicrobial activity against gram+ and gram- other antipsychotics potentially inappropriate. The bacteria. Peptide sequencing reveals the presence of US National Parkinson’s Foundation categorized Ascaris suum anti-bacterial factor epsilon (ASABF- antipsychotics as first line (quetiapine and ε) in A. suum larval ESP, previously described only clozapine), second line (other atypical at the transcriptional level in adult A. suum in antipsychotics) or third line (typical antipsychotics). culture. We determined the number of beneficiaries co- Conclusion: Preliminary results indicate nematode prescribed ≥ 30 days supply of both antipsychotic ESPs possess potent antimicrobial activity. and antiparkinson medications, type and dose of Furthermore, this is the first report of ASABF-ε medications and predictors of potentially present in A. suum ESPs, suggesting its contribution inappropriate prescribing. to observed antimicrobial activity. Ongoing efforts Results: 3838 beneficiaries were dispensed an are aimed at characterizing specific factors antiparkinson medication, with 554 (14.4%) also responsible for observed antimicrobial activities and using an antipsychotic. Approximately 40% of whether these factors interfere with invasion and prescribed antipsychotics were first line (quetiapine replication of pathogenic bacteria. Future studies and clozapine). 27.7% were second line will explore the mechanisms of interference and (aripiprazole, olanzapine and risperidone) and 32.3% therapeutic potential of nematode-derived of the antipsychotics prescribed were potentially antimicrobials in infectious disease models. inappropriate. The global Wald chi-square test showed that an association between first choice

From Drug Discovery to Health Outcomes: Population to Patient | 99s

therapy and age group was statistically significant with quality scores ranging from 1-14 out of 29. (p=0.0182). Patients 80-84 years had an odds ratio Free compared to paid apps scored significantly of 2.2 (95% CI 1.1 -4.4) vs. 66-69 years. The odds higher in analytical features, quality assurance, and ratio of first choice therapy was 1.835 (95% CI 1.31- aggregate quality score. Seventeen apps had a 2.58) for men compared to women. privacy policy, and 38 apps were updated in the past Conclusions: 62.7% of patients receiving year. Few apps allowed BP goal-setting(n=9), antipsychotics received first or second line therapy reminders(n=19), tracked exercise(n=9) or diet(n=6). with 32.3% receiving therapy deemed potentially When BP readings were in alert ranges, only 4 apps inappropriate. Further work is needed to determine suggested an appropriate course of action. There was the reasons for the gap between guidelines and a positive correlation between apps that had prescribing, and to determine strategies for medication or weight tracking; BP categories; improvement. statistical analysis, with a higher aggregate quality Disclaimer: “This study is based in part on de- score(P<0.001). identified data provided by the provincial Conclusions: HTN self-management applications ministries/departments of health. The interpretation range in quality and functionality. The average app and conclusions contained herein do not necessarily was of poor quality and few contained an represent those of the provincial governments or educational component. Even apps with an ministries/departments of health. We acknowledge educational component often had unreliable quality. Health Data Nova Scotia for making the data Thus, there is opportunity for leaders in available” hypertension management to develop a high quality, Acknowledgement: Sara Rehan is the recipient of evidence-based application targeted to Canadians. 2016 GSK/CSPS National Undergraduate Student Acknowledgement: GSK/CSPS National Research Program Award. Undergraduate Student Research Program Award Recipient, presented at the University of Alberta Faculty of Pharmacy and Pharmaceutical Sciences 63. An Evaluation of the Quality of iPhone 2015 Research Day held on November 27, 2015. Applications for Hypertension Self- Management 64. How is Uncertainty in Risks and Benefits Amanda Leong, and Mark Makowsky. Presented in Patient Decision Support Faculty of Pharmacy and Pharmaceutical Sciences, Interventions? University of Alberta, Edmonton, Alberta, Canada Madelaine Bell1, Alysa Pompeo1, Mark Harrison1, Purpose: Patient-oriented HTN applications vary Nick Bansback2. significantly in functionality, from tracking blood 1Faculty of Pharmaceutical Sciences, UBC, pressure(BP) to education. It is critical to identify Vancouver; 2School of Population and Public higher quality HTN self-management applications Health, UBC, Vancouver, Canada that could help patients. The primary objective was to review the quality of HTN self-management apps Purpose: Overtreatment, including treatment that included BP logs. misaligned with patient preferences, is a source of Methods: The Canadian Apple App Store was waste contributing to healthcare unsustainability. searched May 22 - July 28, 2015 using the keywords Patient decision support interventions (PDSIs) aim hypertension and blood pressure. HTN apps were to improve patients’ knowledge and yield choices given an aggregate quality score(max score:46) after more aligned with patients’ preferences. The appraisal of functional characteristics, BP tracking International Patient Decision Aid Standards features, data validation, analytical features, and (IPDAS) group recommend that uncertainty in content trustworthiness. Apps with an educational evidence be described, but provide limited guidance component were given an educational quality on how. There are two levels of uncertainty: 1st score(max score: 29). order, which is the randomness of future events (i.e. Results: Of 902 apps screened, 71 were analysed (n: the risk), and 2nd order, the imprecision in risk 36 paid, average cost CAD$1.95[SD: $1.16]). The estimates. We sought to understand how uncertainty mean aggregate quality score was 16.8(SD: 6.8). is described in PDSIs and highlight heterogeneity in Thirteen apps contained an educational component, approaches to presenting uncertainty due to a lack of

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clear recommendations. who experience moderate to severe pain. Methods: We reviewed all uncertainty statements Objectives: To describe the effects of cannabis use around risks and benefits within all PDSIs available in 30 patients suffering from Crohn's Disease (CD). in three registries (Ottawa Hospital Research The study was performed in an Israeli clinic and the Institute, Choosing Wisely, Option Grid blood samples analysis has been performed in my Collaborative). We developed a framework to lab. classify these statements by their presentation of Methods: In this retrospective observational study uncertainty, and their alignment with IPDAS we examined disease activity, use of medication, guidance. need for surgery, and hospitalization before and after Results: 425 PDSIs were included. The PDSIs cannabis use in patients with CD. Disease activity reviewed ranged in the number of options they was assessed by the Harvey Bradshaw index for presented to people from 2 to 16, and in the number Crohn’s disease. of harms (0 to 31) and benefits (0 to 16) they Results: The average Harvey Bradshaw index included. The number of harms described improved from significantly in 2/3 of patients. outweighed the benefits. The predominant method of Conclusions: The results indicate that cannabis presenting first order and second order uncertainty may have a positive effect on disease activity, as was qualitative. When first and second order reflected by reduction in disease activity index and uncertainty was combined, there were multiple ways in the need for other drugs and surgery. Prospective of describing uncertainty. This study examines the placebo-controlled studies are warranted to fully percentage of statements of uncertainty that met evaluate the efficacy and side effects. In addition, IPDAS guidelines and addresses the considerable the misuse of alcohol in patients taking medical variation in conformity. cannabinoids can be deadly. Conclusion: There is considerable heterogeneity in Given the legal status of marijuana, differences in the methods used to convey uncertainty around risks cannabinoid concentrations across strains of and benefits to patients. This heterogeneity is a cannabis, the lack of information about potential product of a lack of evidence about how best to drug-drug interactions, alcohol misuse and communicate uncertainty. There is an urgent need cannabinoids' interaction, it is the role of for more research into the evaluation of methods for pharmacologists-toxicologists to work with communicating uncertainty to patients and its impact physicians to monitor the use of cannabinoids. on patient preferences. 1 - evaluate the interaction of alcohol in medical Acknowledgement: Madelaine Bell is the recipient cannabinoids; of 2016 GSK/CSPS National Undergraduate Student 2 - negotiate ethical problems in using medical Research Program Award. cannabinoids and their therapeutic monitoring; 3 - identify hepatocytotoxicity as a result between misuse of alcohol when using other therapeutics and 65. Alcohol Misuse and Medical Cannabinoids medical cannabinoids. Use: Interactions Clinical Toxicology Aspects

Manuela G Neuman, Ph.D., In Vitro Drug Safety and Biotechnology Laboratory, Department of Pharmacology and Toxicology, University of Toronto, Canada

Purpose: Cannabinoids are derived from the Canabis sativa which contains more than 60 cannabinoids. The primary psychoactive cannabinoid is delta-9-tetrahydrocannabinol (THC, dronabinol). THC interacts with cannabinoid-like ligands as well as multiple receptors in both the periphery and central nervous system. A spray containing THC and cannabidiol, nabiximols, is approved in Canada as adjunctive analgesic treatment in adult patients with advanced cancer

From Drug Discovery to Health Outcomes: Population to Patient | 101s

Drug Delivery & Pharmaceutical TEM images confirmed NPs spherical shape. Cell uptake studies showed almost double the uptake of Technology our siRNA-Ab-NP in comparison to the control. Cell viability studies using MTS showed low cytotoxicity. Finally, RT-PCR data showed a significant gene knockdown efficiency by 64.5 ± 66. Development of Antibody-modified Chitosan 5.7% for SART-3 and 47.3 ± 8.9% for hCycT1. Nanoparticles for the Targeted Delivery of Conclusion: Our platform demonstrates potential siRNA Across the Blood-brain Barrier as a utility for the treatment of HIV infection in the Strategy for Inhibiting HIV Replication in central nervous system. Astrocytes Acknowledgment: Karam Al-Bayati is grateful for the GSK/CSPS National Undergraduate Student Karam Al-Bayati, Jijin Gu, Emmanuel A. Ho Research Program Award. Laboratory for Drug Delivery and Biomaterials, College of Pharmacy, Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, 67. Preclinical Efficacy Study of a Canada Podophyllotoxin-carboxymethylcellulose Nanoparticles Against Orthotopic and Purpose: HIV infects brain astrocytes using them as Metastatic Tumors a reservoir. There are currently no approved nanomedicines for the treatment of HIV/AIDS in the Yucheng (Rita) Zhao, Shyh-Dar Li* brain mainly due to the presence of the blood-brain Faculty of Pharmaceutical Sciences, University of barrier (BBB). Utilizing receptor-mediated transport British Columbia, Vancouver, BC, Canada; shyh- systems, nanocarriers can deliver adequate [email protected] therapeutic doses to the brain. SART3 is a cellular gene that encodes Tip110, a protein which regulates Purpose: Podophyllotoxin (PPT) is a highly HIV-1 Tat transactivation. Moreover, hCycT1 efficacious drug against multi-drug resistant (MDR) encodes cyclin T1, which also interacts with Tat to tumors. However, due to its high toxicities and poor activate the elongation of RNA polymerase II. The solubility, it cannot be used clinically. We developed goal of this study was to develop dual antibody (Ab) a nanoparticle (NP) drug delivery system to enhance modified chitosan (CS) nanoparticles (NPs) for the activity of PPT against MDR tumors by modulating targeted delivery of SART3 and hCycT1 siRNA the cellular uptake pathway. across the BBB. Methods: Nanoparticle dosage form of PPT Method: CS-NPs are an ideal delivery vehicles (Celludo) is developed by covalently conjugating because they are biodegradable and have the ability PPT and polyethylene glycol (PEG) with acetylated to open tight junctions. siRNA-loaded CS-NPs were carboxymethyl cellulose (CMC-Ac) via ester formulated via ionotropic gelation with linkages. The optimal composition of the conjugate tripolyphosphate (TPP). NPs were then decorated with a PPT/PEG ratio of 2 mol/mol self-assembled with transferrin (OX26-TfR) and bradykinin b2 into 20 nm particles in saline. The formulation was (BDKRB2) receptor antibodies. The formulation tested for its efficacy and safety against MDR tumor was optimized to the mass ratio of 750:150:25:5 models in mice. The pharmacokinetics (PK) is (CS:TPP:siRNA:Ab). The physicochemical studied properly by measuring the concentrations of properties such as surface morphology, mean released and conjugated PPT in blood. particle diameter, zeta potential, and encapsulation Results: The PK study also showed that the celludo efficiency were investigated. Most importantly, the blood circulation time was significantly extended targeting effect of siRNA-Ab-NP was evaluated in compared to the free drug, with a 22.9 times higher U138-MG cells. siRNA knockdown efficiency was half life, 3110 times higher area under the volume of determined at mRNA levels. distribution, 15.9 times higher maximum Results: Our CS-NPs have an average size of 249.6 concentration and 26.3 times higher mean residence ± 5.4 nm and a zeta potential of -40.04 ± 0.16 mV. time, and substantially lower value of the clearance. CS-NPs showed a great siRNA stability and Celludo also was found to be highly efficacious entrapment efficiency as determined by against 4T1 orthotopic breast cancer in mice. electrophoresis and PicoGreen assay, respectively. Celludo treatment resulted in a 97% growth

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inhibition of the primary tumor and complete containing suitable stabilizer were prepared at elimination of lung metastases compared to 40% and desired concentrations. PLGA nanoparticles were 55% tumor growth inhibition and 8.5% and 6.8% formed by controlled nanoprecipitation achieved by lung metastasis with native PPT and CBZ treatment precise control over the microfluidic mixing of two- respectively. In another model, lung metastasis was inlet fluid streams containing PLGA in acetonitrile induced by i.v. injection of EMT6-AR1 cells. and aqueous solutions of stabilizer, through Significant Celludo localization was found in the proprietary staggered herringbone mixing (SHM) metastatic nodules in the lungs compared to normal apparatus. Coumarin-6 was loaded into PLGA lung and other tissues. nanoparticles at desired drug:polymer (w/w) ratios. Results: Microfluidic mixing enabled the rapid and consistent manufacturing of PLGA nanoparticles having stable diameters as low as 70 nm. Single variables, such as aqueous:organic flow rate ratio (FRR), total flow rate (TFR), and PLGA concentration were found to have a significant impact on the size of the resulting nanoparticles. For example, an increase in the PLGA concentration led Conclusion: The 20 nm particles (Celludo) showed to an increase in nanoparticle size whereas enhanced PK and exhibited 5- to 20-fold increased increasing the TFR led to a decrease in nanoparticle tumor delivery and significantly improved efficacy size. Coumarin-6 was successfully loaded into against subcutaneous models of MDR tumors in PLGA nanoparticles with an encapsulation mice compared to, native PPT and the standard efficiency above 70%. taxane chemotherapies, with minimal toxicity. Conclusions: Herein, we have successfully demonstrated the potential of microfluidics technology in the manufacture of PLGA 68. Production of Size-Tunable PLGA nanoparticles for delivery of small molecule Nanoparticle Drug Delivery Systems using therapeutics. Microfluidic Technology

Shyam Garg, Anitha Thomas, Jagbir Singh, Gesine 69. Microfluidics-Based Seamless Manufacture of Heuck, Shell Ip, Tim Leaver, Andre Wild, James RNA-Lipid Nanoparticles from Discovery to Taylor, and Euan Ramsay. Clinic Precision NanoSystems, Inc., Vancouver, BC, Canada Keara Marshall, Suki Sidhu, Mark Ma, Thanos Kritharis, Dounia Droubi, Shyam Garg, Eric Ouellet, Purpose: Conventional methods for producing Anitha Thomas, Tim Leaver, Andre Wild, James PLGA nanoparticles pose numerous challenges such Taylor, Euan Ramsay. Precision NanoSystems, Inc., as maintaining stable diameters below 100 nm, Vancouver, BC, Canada reproducibility, and scale-up. The NanoAssemblr™ platform provides an automated microfluidics-based Purpose: Recently, lipid nanoparticles (LNPs) have technology capable of reproducible, and scalable gained interest in gene therapy as safe and efficient manufacture of nanoparticles. Here, we describe the vectors for delivery of nucleic acids. However, the production of PLGA nanoparticles using the translation of these nanoparticles from the screening NanoAssemblr™ microfluidic platform. We further phase to clinical nanomedicine candidates has been describe strategies to tune the size of the limited due to challenges in optimization during nanoparticles and investigate the encapsulation of a scale-up. Here, we describe the ease in hydrophobic model drug Coumarin-6. manufacturing siRNA-LNPs using the Method: PLGA nanoparticles were manufactured microfluidics-based platform from discovery by microfluidic mixing using the NanoAssemblr™ through pre-clinical development. bench-top instrument (Precision NanoSystems, Inc., Methods: siRNA was encapsulated into LNPs using Vancouver, Canada). PLGA of varying molecular the NanoAssemblr™ Benchtop instrument weights were dissolved in acetonitrile at desired (Precision NanoSystems, Inc., Vancouver, Canada) concentrations. Similarly, aqueous solutions at desired aqueous:organic flow rate ratio and total

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flow rate. Using the same parameters, siRNA was Method: siRNA was encapsulated into LNPs using encapsulated into LNPs using a small volume a single microfluidic mixer on the NanoAssemblr™ discovery instrument and a large volume pre-clinical Benchtop instrument (Precision NanoSystems, Inc., development instrument. The siRNA-LNPs were Vancouver, Canada) at varying aqueous:organic characterized for their size, PDI, and encapsulation flow rate ratios and total flow rates to reach an efficiencies across the three NanoAssemblr™ optimized formulation. The optimized formulation instruments. In further studies, knockdown of target was transferred to a scale-up system comprising a genes using siRNA-LNPs was investigated in continuous flow pumping system with 8 single- primary mixed cortical neuronal cultures. mixer microfluidic chips arrayed in parallel using a Results: siRNA was successfully encapsulated into manifold. This scale-up system utilizes parallelized LNPs across the NanoAssemblr™ platform. LNPs microfluidic mixers to maintain identical reaction prepared using the NanoAssemblr™ Benchtop conditions and increase production throughput. The instrument exhibited small size (~ 50 nm), and low initial version of the NanoAssemblr™ Scale-up PDI (< 0.1) which was similar to siRNA-LNPs GMP system is designed to manufacture 5.75L per prepared using the low volume discovery instrument hour and incorporates a disposable fluid path and the pre-clinical development instrument. eliminating the need for costly and time consuming Encapsulation efficiency of siRNA in LNPs was cleaning validation. similar (> 95%) across all three NanoAssemblr™ Results: siRNA-LNPs prepared using a single mixer instruments. This provides for the seamless scale-up at total flow rate through the microfluidic chip of 12 of optimized conditions from the discovery phase mL/min showed similar size and PDI compared to (100 - 1000 μL), to the benchtop instrument (1 mL - siRNA-LNP made using 2x microfluidic chips and 15 mL), up to the pre-clinical stage (10 mL - 1000 4x microfluidic chips arrayed in parallel. Size and mL). In further studies, siRNA-LNPs manufactured PDI of siRNA-LNPs produced using the single using the NanoAssemblr™ platform showed mixer NanoAssemblr™ Benchtop instrument was effective knockdown (> 75%) of the target gene similar to that produced using the 8x scale-up PTEN in primary mixed cortical neuronal cultures at system further validating the use of microfluidic low siRNA concentrations of 100 ng/mL. parallelization as a mechanism for rapid and Conclusions: The results exhibit the potential of the seamless scale-up. NanoAssemblr™ microfluidics-based platform to Conclusion: This study reflects the potential of aid in the seamless scale-up of RNA-LNPs from microfluidics-based technology in bridging the gap discovery to clinic. from discovery to clinic for nanoparticle-based delivery vectors.

70. Microfluidics-Based Platform for the Scale- up of Lipid Nanoparticles for Delivery of 71. Lanthanide Compounds for the Treatment of Nucleic Acid Therapeutics Bone Density Disorders

Kevin Ou, Jagbir Singh, Gesine Heuck, Shell Ip, Meghanne Rieder+, Jacqueline Cawthray+, David Shyam Garg, Eric Ouellet, Anitha Thomas, Tim Weekes*, Munawar Mohammed+, Jaweria Syeda+, Leaver, Andre Wild, James Taylor, Ray Lockard, Ellen Wasan+, Dave Cooper+, Chris Orvig*, Kishor Euan Ramsay. Precision NanoSystems, Inc., Wasan+ Vancouver, BC, Canada +College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, SK; *Medicinal Inorganic Purpose: Recently, lipid nanoparticles (LNPs) have Biochemistry, University of British Columbia, gained interest as efficient carriers for delivery of Vancouver, BC. nucleic acids. However, their transition from bench to clinic has been slow due to numerous challenges Purpose: Bone is constantly being remodelled such as poor reproducibility and scalability. Here, through the process of bone formation and bone we bridge that gap by describing the robust resorption by osteoblasts and osteoclasts, manufacture of LNPs using the microfluidics-based respectively. An imbalance in this remodelling NanoAssemblr™ platform, and the ease in scaling process preferentially favouring bone resorption production to clinical-scale through microfluidic results in decreased bone mineral density, seen in mixer parallelization. bone density disorders such as osteoporosis.

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Lanthanum (La) is a pharmacotherapeutic agent of 72. Topical Nifedipine for the Treatment of interest because it preferentially accumulates in bone Raynaud’s Syndrome tissue, stimulates osteoblast proliferation and inhibits osteoclast activity. This is anticipated to be a Munawar Mohammed, Jaweria Syeda, Joshua more effective multi-pronged approach than Poteet, Deborah Mitchell, Ed Krol, Supratim Ghosh, currently available therapies like bisphosphonates. Jacqueline Cawthray and Ellen Wasan Preliminary in vitro and in vivo data has shown that College of Pharmacy and Nutrition, University of our novel La compounds exhibit good Saskatchewan, Saskatoon, SK bioavailability, biocompatibility, and are incorporated into the bone matrix, unlike Purpose: Raynaud’s syndrome causes arteriolar bisphosphonates which are only surface-bound to vasospasm upon cold exposure, with fingers and bone. toes most commonly affected. Nifedipine, a Methods: We have performed an acute 1-month oral vasodilator and calcium channel blocker is the drug dosing study of 2 La compounds, La(XT) (in of choice in treating Raynaud’s syndrome. Daily oral aqueous solution) and La(dpp)3 (as CMC suspension administration of nifedipine to reduce the number or lipid formulation) to assess the bone-uptake of and severity of attacks can cause adverse effects lanthanum, the effect on bone mineralization and such as headache and dizziness, therefore a topical architecture, and the biodistribution and toxicity of formulation is a desirable alternative. Nifedipine is the compounds. The biodistribution of La within poorly water soluble and subject to rapid plasma, organs, and the femur was determined via photodegradation. A topical o/w emulsion was ICP-MS, while initial spatial mapping of lanthanum formulated. In order to further improve the within bone was performed by K-Edge subtraction photostability, rutin, quercetin or butyl imaging using the BMIT 05B1-1 beamline at the methoxydibenzoylmethane (BMDBM) alone or in Canadian Light Source (Saskatoon). combination were incorporated. Results: In vivo evaluation indicates that both Methods: Nifedipine emulsions were exposed as lanthanum compounds are well-tolerated at thin films to UVA light (450 W/cm2). Drug analysis 50mg/kg, lanthanum is rapidly cleared from the was performed by RP-HPLC. Mass spectrometry plasma, and, most importantly, targets bone tissue was done using a Triple Quadrupole/Linear Ion trap and exhibits a depot type of accumulation. mass spectrometer with an electrospray ionization source. Physical stability was determined by 3+ accelerated sedimentation using a photocentrifuge La distribution in (LumiSizer) at 42°C over 12h. Permeation studies

rat femur - oral… were performed at 32°C in static vertical diffusion 3+ cells holding StratM model skin membranes. 500 Proximal Results: Rutin at 0.5% (w/w) did not improve the stability of nifedipine to UVA light, however Mid 0 quercetin at 0.5% (w/w) and BMDBM at 3% (w/w) Distal alone or in combination maintained nifedipine ppb (ng/g) ofLa concentration (>70%) after 4h UVA exposur.e Mass spectrometry analysis indicated dehydronifedipine Conclusion: Two lanthanum-based lead compounds and dehydronitrosonifedipine are the primary were examined as a potential therapeutic agent in the nifedipine photodegradation products formed, treatment of bone density disorders. It was shown regardless of photostabilizer incorporated. that La accumulates in the bone after dosing, with Sedimentation analysis by photocentrifuge showed LaXT showing slightly higher uptake. The current slight differences in tendency to phase separation at study suggests that chronic in vivo experiments need 42°C over 12hr between the emulsions containing to be performed to assess their drug candidacies, the various photostabilizer additives. Assessment of with the long-term goal of transfering these nifedipine diffusion across artificial skin membranes treatments for human use. indicated that all of the formulations enabled Acknowledgement: Meghanne Rieder is a winner nifedipine diffusion, with the nifedipine-quercetin of the GSK/CSPS National Undergraduate cream showing greatest cumulative diffusion over marcStudent Research Award 4hr. Conclusions: We have prepared stable topical

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nifedipine emulsions with demonstrated 74. Isolation of Primary Murine Brain photostability that promote nifedipine uptake across Endothelial Cells, Pericytes and Astrocytes model skin. Florian Bernard1,2, Hania Kebir2, Marc André Lécuyer2, Alexandre Prat2, Grégoire Leclair1, V. 73. Evaluation of Carbopol 934P NF Gaëlle Roullin1 Microemulsion-Based Gel Formulations for 1Axe d’Analyse et Formulation du Médicament, Topical Drug Delivery of Diclofenac Sodium Faculté de Pharmacie, Université de Montréal; 2Laboratoire de Neuro-immunologie du Centre de Bra’a M. Hajjar, Kira-Isabel Zier, Shirzad Azarmi, Recherche du CHUM, Université de Montréal, Raimar Loebenberg* Montréal, Québec, Canada. Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Alberta, Edmonton, Canada Purpose: In vitro models of the blood-brain barrier (BBB) are essential tools for screening drugs Purpose: The aim of the current research work was targeted to the central nervous system. Although to improve the transdermal delivery of diclofenac several useful cell-based BBB models have been sodium, a poorly water-soluble drug. Different developed, factors related to their complexity, cost formulations were prepared and vitro evaluated. and time limit their application for drug transport Methods: A micro emulsion (ME) was prepared studies. Therefore, we sought to develop a simple, using Labrasol, Transcutol P and Lauroglycol FCC. versatile, reproducible and biorelevant tri-cellular- For enhancing the viscosity, Carbopol 934P NF was based BBB model, using murine primary brain used to form an ME-based gel. The prepared endothelial cell (EC), pericyte and astrocyte cultures. formulations were characterized for physical Methods: ECs were isolated from brain capillaries appearance, droplet size, Zeta potential, Freeze-thaw of 8-12 week old wild-type C57BL/6 mice, whereas cycle, phase separation, pH, conductivity, drug pericytes and astrocytes were prepared from the content, staining solubility test, transmission brains of 1-5 day old mice. We used a simple 3-step electron microscopy and in-vitro drug release using protocol that consisted of mincing/homogenizing the Franz diffusion cells. One-way ANOVA and brain. Next, the homogenate was digested and brain Tukey’s test were used to establish statistical microvessels were separated by Percoll gradient significance at p>0.05. A comparison between a centrifugation. Brain capillaries were seeded onto commercial formulation and a Carbopol gel appropriate supports. Three different media, specific containing free drug only are presented. to the culture of each cell type, were used. The Results: Mean droplets size for ME and ME-based purity of EC, astrocyte and pericyte cultures was gel-systems were 114.4 0.472 nm, and 178 2.46 assessed by flow cytometry and nm respectively, whereas the zeta potential values immunocytochemistry. The trans-endothelial were -33.3  0.64 mV for the former and -33  0.40 electrical resistance (TEER) of EC cultures was mV for the latter. No significant variation in the pH evaluated with the ECIS System (Applied and no physical appearance alterations has been BioPhysics). observed after subjecting the formulations for Results: Highly enriched EC cultures were obtained stability tests. Further, TEM images for drug-loaded 7 days post-plating following addition of ME and its gel exhibited nano-droplets that were puromycine to the culture medium. These cells almost spherical in shape. The release rate of expressed the endothelial markers MCAM and diclofenac sodium formulated as ME or as ME gel PECAM. They displayed high TEER values (4000 had the highest release values (76.67 ± 8.63% and Ω), suggesting establishment of tight junctions. EC 69.28 ± 7.14 % after 6 hr) respectively. This was cultures responded to inflammatory stimuli (TNF) statistically significant (p 0.0001) compared to the by upregulating their expression of the cell adhesion control and the marketed formulation. molecule ICAM-1. Pericytes and astrocytes were Conclusion: The result suggested that both ME successfully obtained and enriched from the brains systems are potential vehicles for penetration of newborn mice. They were cultured for 3-5 weeks, enhancement of diclofenac sodium as a topical at which time they expressed specific markers delivery system. However, the ME-based gel seems MCAM and PDGFR-β for pericytes and GFAP and to be preferable due to its pH profile and higher GLAST-1 for astrocytes. viscosity to be handled as topical dosage form. Conclusion: We successfully isolated three major

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constituents of the mouse BBB using a single significantly attenuated levels of IL-1β and IL-8 in protocol. All cultured cells retained their biological CVL. features and will now be used to develop a BBB Conclusion We designed a novel non-invasive model. implantable device for delivering HCQ in rabbits intravaginally capable of suppressing N9-induced inflammation and T-cell activation. This non- 75. Hydroxychloroquine Attenuated Vaginal cytotoxic system may be suitable for the evaluation Tissue Inflammation and T-cell Activation in of other drug candidates for sexually transmitted vivo infections.

Yufei Chen1, Yannick L. Traore1, Sidi Yang1, Keith R. Fowke2,3, and Emmanuel A. Ho1 76. pH-Sensitive Nanomicrobicide for the 1Laboratory for Drug Delivery and Biomaterials, Targeted Delivery of siRNA to Vaginal College of Pharmacy; 2Department of Medical Mucosal CD4+ Immune Cells in a Mouse Microbiology and Infectious Diseases, 3Department Model of Community Health Sciences, College of Medicine, Faculty of Health Sciences, University of Sidi Yang, Yufei Chen, Miral Fumakia and Manitoba, Winnipeg, MB, Canada Emmanuel A. Ho Laboratory for Drug Delivery and Biomaterials, Purpose It has been revealed that women with College of Pharmacy, Faculty of Health Sciences, natural resistance to HIV infection demonstrating an University of Manitoba, Winnipeg, MB, Canada immune quiescence (IQ) phenotype of female genital tract, presenting reduced HIV target cells, Purpose: This study aims at developing a pH- low levels of HLA-DR positive activated T cells and sensitive nanomicrobicide for targeted delivery of reduced levels of pro-inflammatory cytokines. We siRNA to intravaginal CD4+ immune cells as a developed a novel biocompatible vaginal implant for prophylaxis to prevent intravaginal transmission of the delivery of the immunomodulatory drug HIV. This technology platform consists of antibody- hydroxychloroquine (HCQ) to induce IQ to evaluate conjugated siRNA nanoparticles (NPs) loaded into a its effectiveness in suppressing Nonoxynol-9 (N9) vaginal gel. induced inflammation and T-cell activation in a Methods: Cy-3 siRNA was condensed by rabbit vaginal mucosal model. polyethyleneimine and encapsulated into NPs using Methods Reservoir-based polyurethane implants biodegradable polymer, poly(lactic-co-glycolic were fabricated via hot-melt injection molding, acid)-polyethylene glycol. NPs were conjugated to embedded with a radio-frequency identification anti-mouse (in vivo)/anti-human (in vitro) anti-CD4 micro-transponder for real-time tracking. The device antibody (siRNA-NPs-CD4) or isotype control (IgG) containing HCQ (60 mg) was non-invasively (siRNA-NPs-IgG). Resulting NPs were formulated implanted in the vaginal tract of New Zealand White into 1% hydroxyethyl cellulose (HEC) gel. rabbits for 6 days and challenged with 1 mL 4% N9 Results: NPs had a particle size of 256.0±7.2nm and gel for 24 hours. HCQ levels and inflammatory a zeta-potential of -15.62±1.64mV in PBS (pH7.4) cytokine production in cervicovaginal lavage (CVL) and a particle size of 271.6±1.8nm and a zeta- was quantitated using HPLC and sandwich ELISA. potential of -8.66±2.43mV in vaginal fluid simulant Levels of RLA-DR (rabbit equivalent of human (VFS, pH4.2). Encapsulation efficiency was HLA-DR) from isolated vaginal mucosal T-cells was 75.6±0.9%. NPs showed a pH-dependent release investigated by flow cytometry. profile, with sustained release of siRNA in PBS Results X-ray analysis showed the implant (pH7.4) (~25% over 14 days) and <1% release of remaining within the rabbit vaginal tract for over 40 siRNA in VFS. siRNA-NPs-CD4 improved siRNA days. HCQ exhibited an average release rate of uptake into CD4+ Sup-T1 cells by 72%, 121% and 10.67 µg/mL per day for 7 days. The expression of 67% respectively compared to siRNA-NP-IgG, 2hr, RLA-DR on isolated vaginal CD4+ and CD8+ T 4hr and 6hr post treatment. In vivo studies revealed cells in N9-challenged HCQ pre-treated rabbits were that the gel formulation improved NP retention in restored to basal levels similar to the naïve group. mouse genital tract by one fold compared to NP Lower amounts of immune cell recruitment were suspension (without gel), 24hr post intravaginal observed in HCQ pre-treated rabbits with administration. The 1% HEC gel loading siRNA-

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NPs-CD4 improved siRNA uptake into intravaginal polymer solutions in water was measured using CD4+ immune cells by 91% compared to 1% HEC inverse flow method, differential scanning gel loading siRNA-NPs-IgG, 24hr post intravaginal calorimetry) DSC ( and rheometrical analysis. administration. An improvement of 81% in the total Results: Optimum condition for the synthesis of siRNA uptake into vaginal tissue was also observed triblock copolymers of maximum yield and desired in mice treated with 1% HEC gel loading siRNA- degree of polymerization for the PCBCL block NPs-CD4 compared to mice treated with 1% HEC (~14) was achieved when 30%wt of biphenyl was gel loading siRNA-NPs-IgG, 24hr post used in the reaction. Copolymers with thermo- administration. responsive behavior at 15 % w/w, have shown Conclusions: We developed a pH-responsive higher polydispersity and branching; irrespective of nanomicrobicide that achieved targeted delivery of the applied method of polymerization. For these siRNA to intravaginal CD4+ immune cells in mice. block copolymers at 15 % w/w, the sol-gel transition NPs had desirable particle size and zeta potential for temperature was 35 °C as measured by inverse flow intravaginal delivery and a pH-dependent release method, DSC and rheometrical analysis. profile that preserved siRNA under acidic Conclusion: The present study illustrates successful environments. By formulating into a gel dosage- use of solution polymerization for the preparation of form, the nanomicrobicide improved retention triblock copolymers based on PEG and within the female genital tract and provided ease in functionalized PCL. We also demonstrated that the administration. PDI of block copolymers can affect their sol-gel transition. Tri block copolymers with a broader molecular weight distribution, showed better sol-gel 77. Thermo-reversible Gels Based on Triblock transition. Copolymers of PEG and Functionalized Caprolactone: The Effect of Polymer Polydispersity on their Gelation Behaviour 78. Derivation and Experimental Validation of Ion-Exchange Model for Loading Anionic Ghasemi N, Vakili MR, Lavasanifar A. Drugs into Cationic Polyacrylate Polymer Faculty of Pharmacy and Pharmaceutical Sciences, Eudragit® RS/RL Films University of Alberta, Edmonton, Alberta, Canada Lily Yi Li1, Kuan Chen1, Jason Li1, Anil Kane2, Purpose: The long term objective of this study is to Xiao Yu Wu1. develop biodegradable stimuli-responsive gels with 1Advanced Pharmaceutics and Drug Delivery optimal properties for depot and smart drug delivery. Laboratory, Leslie Dan Faculty of Pharmacy, In this study, we first developed an optimum method University of Toronto, Toronto, ON; 2Patheon Inc., of solution polymerization for the preparation of Toronto Region Operations (TRO), Mississauga, block copolymers based on poly(ethylene glycol) ON, Canada (PEG) and functionlaized poly(caprolactone) (PCL). We then investigated the effect of polymer Purpose: Cationic polyacrylate polymers, Eudragit® polydispersity on the gelation of triblock copolymers RS and Eudragit® RL (RS/RL), are widely applied prepared by bulk versus solution polymerization. as coating materials for making controlled release Methods: Triblock copolymers of poly(α-carboxyl- dosage forms. Due to drug interaction with the co-benzyl carboxylate-ε-caprolactone)-b-PEG-b- cationic quaternary ammonium groups of the poly(α-carboxyl-co-benzyl carboxylate-ε- polymers, the current diffusion-controlled drug caprolactone) (PCBCL-PEG-PCBCL) were prepared release model is not suitable for describing the through ring opening polymerization of -benzyl-- loading and release kinetics of anionic drugs in caprolacton (BCL) and PEG (1450 kDa) by either RS/RL-coated dosage forms. Therefore, the aim of bulk polymerization or an optimized solution this study is to establish a mathematical model to polymerization method using biphenyl as solvent; predict loading kinetics of anionic drug into RS/RL followed by hydrogenation of block copolymer. films. Prepared block copolymers were characterized for Method: A mathematical model combining ion- their molecular weight, polydispersity index (PDI) exchange and diffusion terms was developed to 1 and branching by H NMR and gel permeation describe the fractional absorption (Mt/M0) over time, chromatography (GPC). The sol-gel transition of where Mt is the amount of drug remaining in the

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external volume at any time and M0 is the initial deoxyribose phosphate from a hairpin amount of drug in the external drug solution. The oligonucleotide if PNKP phosphatase is inhibited. model was verified using theoretical solutions and Identified hit compounds with potent PNKP then validated by experiments. Solutions of inhbitory activity were used for encapuslation in ibuprofen Na or diclofenac Na were incubated with polymeric micelles of different structures. The RS/RL polymer films and concentration was encapsulated drug levels were measured using monitored by spectrophotometry. Effects of model HPLC and the cumulative in vitro release was parameters on drug loading kinetics were analyzed investigated by a dialysis method. The non-specific with computer simulations and experiments in toxicity of the PNKP inhibitors was tested against triplicates. HCT 116 cells using MTS assay. Free and Results: All Mt/M0 curves exhibited gradual decline encapsulated drugs were also tested for their activity and reached the equilibrium plateau around 48 h. in sensitization of HCT 116 cells to irinotecan or The model predicted Mt/M0 profiles matched well radiation. with the experimental curves as evidenced by small Results: Our fluorescent based assay identified three root-mean-square deviation (<0.0782). Model hit compounds namely A12B4C5, A12B4C60 and parameters, e.g. equilibrium binding constant and A12B4C61 as potent inhibitors of PNKP with Kd diffusivity of the drugs in the polymers, were values of 0.13 and 0.16 µM, respectively. Efficient evaluated from the experimental data. Drug loading loading of A12B4C5, A12B4C60 and A12B4C61 efficiency and equilibrium loading level were found was achieved in polymeric micelles, which showed to depend on external conditions, e.g. solution drug: polymer w/w ratios of 1:40. We also measured volume and initial drug concentration. Drug 57.7, 63.4, 66.2 % drug release from polymeric properties appeared to affect loading kinetics. micellar formulations of A12B4C5, A12B4C60 and Conclusion: This work for the first time revealed A12B4C61 within 24 h. The potent inhibitors show the effect of interactions between RS/RL and anionic slight toxicity at doses higher than 20 µM. PNKP drugs on loading kinetics. The kinetics and inhibitors were able to radio/chemosensitize HCT thermodynamic parameters determined from this 116 cells. work would be very useful for prediction of release Conclusions: Our results point to a potential for kinetics of RL/RS coated ionic drug-loaded dosage encapuslated inhbitors of PKNP for sensitization of forms. colon tumors to DNA damaging chemotherapy and radiation.

79. Nano-encapusaltion of Inhibitors of Polynucleotide Kinase/Phosphatase (PNKP) 80. Development of Anti-CD20 Immuno-micelles by Polymeric Micelles for Selective for Active Drug Targeting to Hematological Sensitization of Cancer Cells to DNA Damage Cancer

Zahra Shire, Afsaneh Lavasanifar, Tristan Verdelet, Asma Saqr, Mohammad Reza Vakili, Raymond Lai, Dennis Hall and Michael Weinfeld. Afsaneh Lavasanifar Faculty of Pharmacy and Pharmaceutical Sciences, Faculty of Pharmacy and Pharmaceutical Sciences, Faculty of Science, and Faculty of Medicine and University of Alberta, Edmonton, Alberta, Canada Dentistry, University of Alberta, Edmonton, Alberta, Canada Purpose: The aim of this study was to covalently attach the anti CD20 antibody, rituximab, to the Purpose: The aim of this project is to enhance the surface of the polymeric micelles and assess the outcome of radio and chemotherapy with DNA effectiveness of this approach in enhancing micellar damaging agents in solid tumors through specific interaction with target cells overexpressing development of tumor targted delivery systems for CD20. inhibitors of important DNA repair enzyme, Methods: Rituximab, was coupled to Cy5.5 NHS polynucleotide kinase/phosphatase (PNKP). ester at pH=8. The Cy5.5 conjugated antibody was Methods: A library of polysubstituted coupled to 3-(N-succinimidyloxyglutaryl) imidopiperidine compounds, were screened for their aminopropyl, polyethyleneglycol-carbamyl PNKP inhibitory activity using a novel assay that distearoylphosphatidyl-ethanolamine (NHS-PEG- + prevents release of fluorescent 2-aminopurine DSPE). Cy3-N3 was covalently conjugated to a

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tribockcopolymer, methoxy poly(ethylene glycol)-b- hydrogels (MITCH) that crosslink in situ upon poly(ε-caprolactone)-b-poly(α-propargyl injection via a rapid chemical reaction between two carboxylate-ε-caprolactone) (MPEG-PCL- functionalized polymers offer a potential solution, as PPCL),through click reaction. Mixed micelles were they can be designed to be transparent, degradable, then prepared by incubating Cy5.5 labeled antibody and enable long-term, sustained drug release. modified PEG-DSPE with MPEG-PCL-PPCL-Cy3 However, in order to assess the in vivo capabilities at 1:1 molar ratio overnight. Size, critical micellar of these hydrogels, very small volumes of each concentration (CMC) and kinetic stability of mixed reactive component (1–20 μL) must be injected and micelles (without any cy3 or cy5.5 probes) were no suitable system exists for the administration of measured by zetasizer (DLS measurement) and MITCH hydrogels at low volumes. compared to that for micelles from the individual Methods: We have developed a microinjection polymers. The size and morphology of micelles was device that is capable of mixing two reactive also investigated by TEM. Flowcytometry was used precursor polymers for MITCH hydrogels and to follow the association of plain versus antibody precisely inject volumes of 1-20 μL through a modified mixed micelles with CD20 over expressing narrow capillary suitable for ophthalmic therapies. PTLD cells using fluorescence at 570 and 707 nm, The device involves a double-barrel syringe for Cy3 and Cy5.5, respectively. connected to two inlets of the microfluidic chip, a Results: The formation of mixed micelles was channel with herringbone mixing grooves, and a confirmed by DLS by detecting one peak around volume control reservoir (1-20 μL) with a one-way 65nm for mixed micelles compared to two separate valve connected to second syringe that pushes the peaks around 50.4 and 23.1 nm for micelles of mixed polymer solutions out the capillary. individual polymers. Similar results were also found Results: The device is capable of ejecting hydrogel by TEM. The CMC of the mixed micelle was droplets of controlled volumes (~±15%) in the range 7.8µg/mL; significantly lower than that of NHS- of interest (1–20 μL) via a handheld operation into PEG-DSPE micelle (35.6 µg/mL), and higher than various materials, including bovine vitreous humour that of MPEG-PCL micelle (3.05 µg/mL). Kinetic at 37°C. In vivo experiments involving the injection stability of the mixed micelle was not significantly of fluorescently-labelled poly(oligoethylene glycol different from the MPEG-PCL micelle; however it methacrylate) (POEGMA) MITCH hydrogels, was significantly higher than that of the NHS-PEG- crosslinked via hydrazide and aldehyde chemistry DSPE micelles. Flowcytometry showed higher that react to form degradable hydrazone crosslinks, association of anti-CD20 micelles with PTLD cells into the eyes of Sprague Dawley rats showed no compared to plain micelles and CD20 negative cells significant toxicity relative to controls. Experiments (SUP-M2). showing the release of fluorescently-tagged model Conclusion: The results points to the effectiveness drugs will be performed. of PEG-DSPE/ MPEG-PCL mixed immune micelles Conclusions: Precisely controlled amounts of in modified on their surface with rituximab in situ-gelling MITCH hydrogels were injected in vivo enhancing their association with CD20 into using a newly-developed microinjection device. overexpressing cells. Such a system could clinically exploit the favorable properties of injectable hydrogels as ocular drug delivery materials. 81. Delivering in situ-Gelling Hydrogels for Ophthalmic Drug Therapies Using a Microinjection Device 82. A Gadolinium-Doxorubicin Nanocomplex as a Novel Targeted Drug-Delivery System Scott B. Campbell, Jun Yang, Ben Muirhead, Heather Sheardown, P. Ravi Selvaganapathy, and Zhipeng Yuan1, Linghong Guo2, Shannon Yoo2, Todd R. Hoare Raimar Loebenberg1* and Wilson Roa2* 1Faculty of Pharmacy and Pharmaceutical Sciences, Purpose: Numerous posterior segment ocular University of Alberta; 2Department of Radiation diseases are regularly treated via intraocular Oncology, Cross Cancer Institute, Edmonton, injections, but the frequency of injections required Alberta, Canada for these treatments increases the risk of complications. Mixing-induced two-component Purpose: Anthracycline antibiotics, such as

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doxorubicin, can form complexes with transition 83. First Report of an Intravesical Therapy with metals. Gadolinium as one of those transition metals Activity in a Muscle Invasive Bladder Cancer has been well investigated as a promising T1 Xenograft Model contrast agent for clinical magnetic resonance imaging (MRI). The objectives of this study were to Clement Mugabe1, Moskalev2, Richard Liggins1, establish a reliable method for fabricating Mike Parr3, Igor, Alan So2, Martin Gleave2, doxorubicin loaded gadolinium nanoparticles and Jayachandran Kizhakkedathu4, Donald Brooks4, examine the feasibility of this synthesized Helen M. Burt5 nanoparticles for delivering the antibiotic 1Centre for Drug Research and Development, doxorubicin into human breast cancer MDA-MB- Vancouver; 2Vancouver Prostate Centre, 3Stika 231 cells and having anticancer efficacy Biopharma Inc., Vancouver, BC; 4Centre for Blood subsequently. Research; Vancouver; 3Faculty of Pharmaceutical Methods: Doxorubicin loaded gadolinium Sciences, University of British Columbia, nanoparticles were fabricated by a simple one-step Vancouver BC. homogeneous precipitation method. Synthesized nanoparticles were further characterized by means of Purpose: We have developed a functionalized transmission and scanning electron microscope, nanoparticle formulation of docetaxel to improve dynamic light scattering method as well. Confocal treatment outcomes of intravesical chemotherapy. fluorescence microscope was used to visualize the Based on hyperbranched polyglycerol (HPG) cellular uptake of the nanoparticles by MBA-MD- technology, our new formulation STK-01: a) 231 cells after 24 hours’ incubation. Flowcytometry solubilises the drug without micelle forming experiments were carried out to evaluate the surfactants b) is mucoadhesive, to prolong drug percentage of apoptotic cells after 3-day incubation, residence time, c) enhances drug uptake into the and APC-Annexin V was used as the fluorescence bladder wall d) has demonstrated safety in dye. preclinical models, and e) has shown promising Results: The synthesized doxorubicin loaded efficacy in treating non-muscle invasive bladder nanoparticles possess desirable morphology tumors. The objective of this study was to (sphere), diameters (average size about 150nm) and investigate the effectiveness of STK-01 in a new zeta potential (+13.8 mV). A high doxorubicin mouse model of muscle invasive bladder cancer. loading amount (10.1%, w/w) was achieved. Methods: Mice were inoculated with UM-UC3-luc Confocal micrographs show our nanoparticles were using ultrasound-guided intramural injection and actively taken up via endocytosis by MDA-MB-231 tumor growth was measured by bioluminescence human breast cancer cells. A dose-dependent trend imaging twice a week. On day 8 post-tumor in the percentage of apoptotic cells of nanoparticles inoculation, mice with established muscle invasive treated groups was detected by flowcytometry assay. bladder tumors were grouped into 3 treatment Conclusion: A novel doxorubicin loaded spherical groups and were instilled with 50 µL of PBS gadolinium nanoparticle system was developed with (control), or 50 µg of docetaxel in Polysorbate 80 good cellular uptake profile and promising (Taxotere), or 50 µg of docetaxel formulated in HPG therapeutic efficacy. Gadolinium based nanoparticles (STK-01). nanoparticles and chelates were reported as T1 Results: All mice developed bladder tumors and the contrast agent for clinical MRI, which means our success of tumor implantation was confirmed by doxorubicin gadolinium nanoparticles have a great bioluminescence and ultrasound imaging. potential for working as a multifunctional platform Intravesical therapy with STK-01 significantly and personalized medicines. (p<0.001) inhibited tumor growth compared to the Taxotere treatment group. There was also a significant difference in tumor growth between the STK-01 treated group and the PBS control group. There was no significant difference between the Taxotere treated group and the PBS control group. Conclusion: A novel formulation of docetaxel (STK-01) was found to be safe and effective when given intravesically to treat muscle invasive tumors in mice. To our knowledge, this is a first report of an

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intravesical therapy showing activity in a muscle- MDR EMT6/AR1 cells, respectively, in contrast to invasive bladder cancer model. Our data suggest that DMPLN with 28% and 0% cell kill in ETM6/WT intravesical chemotherapy with STK-01 may and EMT6/AR1. Moreover, DMPLN showed only provide a viable bladder-sparing treatment comparable DOX uptake to free drug cocktails, alternative for patients with muscle invasive bladder whereas DMPLN-DHA exhibited nearly 3- and 5- cancer who are medically unfit for cystectomy. fold higher cellular DOX uptake with strong DOX fluorescence signal co-localized with nuclei stained by DAPI in EMT/WT and EMT6/AR1 cells, 84. 120 Encapsulation of Docosahexaenoic Acid respectively. in Polymer-Lipid Hybrid Nanoparticles Conclusion: The DHA-containing PLN system Enhance Efficacy of Co-delivered Synergistic provides a novel strategy to enhance intracellular Drug Combination in Multidrug Resistant drug delivery across the rigid plasma membrane in Breast Cancer Cells MDR cancer cells for improved nanomedicine chemotherapy. Rui Xue Zhang, Lily Yi Li, Xiao Yu Wu. Advanced Pharmaceutics and Drug Delivery Laboratory, Leslie Dan Faculty of Pharmacy, 85. Polymer-Lipid Based Nanomedicine of University of Toronto, Toronto, Ontario, Canada Synergistic Drug Combination for Improving Chemotherapy of Multidrug Resistant Breast Purpose: Nanoparticles have exhibited enhanced Cancer cytotoxicity against multidrug resistant (MDR) cancer cells. However, increased membrane rigidity Rui Xue Zhang, Xiao Yu Wu. in some MDR cancer cells impairs drug uptake and Advanced Pharmaceutics and Drug Delivery endocytosis of nanoparticles, thus reducing the Laboratory, Leslie Dan Faculty of Pharmacy, efficacy of chemotherapy. This overlooked MDR University of Toronto, Toronto, Ontario, Canada mechanism has been observed by our group and others. But the strategy to circumvent this drug Purpose: Chemotherapy is a primary treatment delivery barrier has not been fully explored. The modality for metastatic cancer. However, the present work is aimed to investigate whether development of multidrug resistance (MDR) limits encapsulating unsaturated fatty acid the efficacy of chemotherapy. Drug combination docosahexaenoic acid (DHA) together with regimens that target multiple cellular mechanisms of synergistic doxorubicin and mitomycin C MDR are frequently used in the clinic to enhance combination in a polymer-lipid hybrid nanoparticle cancer chemotherapy. Unfortunately, dissimilar (DMPLN-DHA) would enhance drug uptake and pharmacokinetics and tissue disposition of different cytotoxicity of DMPLN without DHA in MDR drugs in free solution compromise the therapeutic breast cancer cells. effectiveness of combination therapy and increase Method: Both DMPLN and DMPLN-DHA were normal tissue toxicity. The aim of this study is to formulated using oil-in-water simultaneous self- evaluate polymer-lipid hybrid nanoparticles (PLN) assembly process. Clonogenic assay was used to as an emerging nanoparticle system for determine the cytotoxicity of free drug spatiotemporal co-delivery of synergistic drug combinations, DMPLN and DMPLN-DHA against combination to tumor tissue and cancer cells for both drug sensitive EMT6/WT and MDR enhanced efficacy in treating MDR breast cancer. EMT6/AR1 murine breast cancer cells. Intracellular Method: PLN co-loaded with a synergistic ratio of localization of DOX after 4 h treatment with free doxorubicin (DOX) and mitomycin-C (MMC) drug cocktails and PLN formulations with and (DMPLN) was formulated using the single-step without DHA were visualized under a fluorescence sonication method followed by oil-in-water microscopy at λem 488 nm/λex 588 nm. The cellular simultaneous self-assembly. Intracellular uptake and DOX fluorescence was quantitated by Image J. localization of DOX delivered in various Results: Compared to DMPLN, DMPLN-DHA formulations in MDR EMT6/AR1 breast cancer cells significantly enhanced cytotoxicity in both were determined by confocal fluorescence EMT6/WT and EMT/AR1 cells. At low drug microscopy. Pharmacokinetics and tumor concentrations (0.1-1 μM), DMPLN-DHA achieved accumulation of DMPLN were evaluated in a as high as 91% and 66% cell kill in EMT6/WT and murine orthotopic breast tumor model. Tumor

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apoptosis was evaluated by immunohistochemical (Glumetza®). staining of caspase-3 activation. Results: The size of our dosages in SGF was Results: DMPLN enhanced intracellular DOX slightly increased, but then remained stable and the accumulation and localized nuclear distribution tablet integrity was maintained, suggesting that they compared to free DOX and clinically used will be able to pass through the pylorus into the PEGylated liposomal DOX (PLD, Caelyx®) in MDR intestinal tract. The Metformin was released not only cancer cells. Compared to free DOX-MMC cocktail, in the stomach and upper intestine, but also in the DMPLN prolonged systemic circulation and co- whole intestinal tract including the colon. The delivered high concentrations of DOX and MMC at liberation patterns in simulated gastric (SGF) and effective ratios into the tumor over at least 24 h. As a intestinal (SIF) fluids showed the new modified- result, DMPLN demonstrated higher tumor cell release tablet forms presented good shape and apoptosis compared to the free DOX-MMC release kinetics during 2h in SGF and 6h in SIF combination and PLD (Caelyx®). dissolution. A thick gel formation surrounding the Conclusion: DMPLN enabled ratio-metric delivery tablet was observed probably contributing to the of synergistic DOX-MMC combination to the tumor controlled release of Metformin. site and provided sustained local drug bioavailability The in vitro kinetic profiles and the in vivo study to MDR cancer cells. These findings suggest PLN as showed no marked pharmacokinetic differences an efficient platform for nanoscale drug delivery of between our monolithic metformin formulation with synergistic drug combination and substantiate the Ca-CMC/MC and the Glumetza® reference. importance of rational design of nanomedicine for Conclusion: The new monolithic system can improved chemotherapy cocktail. efficiently control the highly soluble metformin. The dry compaction end coating free procedure allows a low cost to manufacture. 86. Controlled Delivery System for Highly Soluble Active Ingredients: The Case of Metformin Pharmaceutical & Analytical Canh Tien Le and Mircea Alexandru Mateescu Department of Chemistry and Centre Pharmaqam, Chemistry Université du Québec à Montréal, Montreal, Québec, Canada

Purpose: Despite the huge efforts to formulate 87. Hypoxia-Activated SN-38: Targeting Hypoxic highly soluble drugs for controlled delivery, there is Tumors still a need of pharmaceutical forms easy to process and using safe excipients. A commercial sustained Dinghua Liang, Geoffrey K. Tranmer release form of Metformin is a bilayer system: a College of Pharmacy, University of Manitoba, swollen Gastro-Retention Dosage Form (GRDF) Winnipeg, MB, Canada providing up to 6h retention in stomach and continuous local (stomach and upper intestine) Purpose: Solid tumors are commonly subject to release that may generate a saturable absorption. Our hypoxia because of the inadequate oxygen supply main objective was, using Metformin as drug model, caused by abnormal vasculature and irregular blood to realize a pharmaceutical device able do deliver perfusion in solid tumors. Hypoxic cancer cells have highly soluble active principles to the expected undesirable properties such as a high tendency to absorption windows. metastasize and resistance to chemotherapy and Methods: The excipients of the novel release system radiotherapy. An agent against hypoxic cancer cells were methylcellulose (MC) homogeneously is thus necessary to hold these malignant cells in distributed in a calcium-carboxymethylcellulose check. Hypoxia-activated prodrugs of SN-38 (the (CaCMC) dry powders with metformin as model active metabolite of Irinotecan) are therefore drug. By direct compression, monolithic, coating- designed and synthesized to target hypoxic cancer free devices have been characterized in vitro. An in cells. vivo study on beagle dogs was conducted in Methods: The anti-cancer activity of SN-38 can be comparison with an extended-release formulation masked by attaching a substituted benzylic trigger

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on SN-38’s 10-OH, creating a substituted benzyl-O- and chiral columns after methyl esterification of SN38 ether. The conversion of the substituent on the HETEs. Therefore, the aim of the current work is to benzylic trigger from an electron-withdrawing group develop a reverse-phase liquid chromatography (EWG) to an electron-donating group (EDG) (i.e., method for the stereoselective determination of from EWG-Ph-CH2-O-SN38 to EDG-Ph-CH2-O- HETEs. SN38) can consequently result in the discharge of Methods: HETEs were esterified at the chiral center SN-38 as the activated anti-cancer agent. In hypoxic with (+)-O,O′-diacetyl-L-tartaric anhydride tumors, an electron-withdrawing nitro group can be (DATAAN) to from HETE-DATAAN reduced by certain 1-electron reductases to a radical diastereoisomers. Thereafter, HETE-DATAANs anion in reductive environments only, and can be were separated using a gradient elution of water- subsequently reduced to an electron-donating acetonitrile-methanol-isopropanol-ammonium hydroxylamino group; thus nitrobenzyl groups have formate mixture using reverse phase C18 column at been selected as the trigger for hypoxia-activated 30°C. Both single-ion and multiple-reaction- SN-38. Synthetic approaches exploiting a variety of monitoring (Waters Micromass ZQ 4000 alkylating agents such as mesylates, bromides and spectrometer and AB Sciex QTRAP 2000) were alkylating method such as Mitsunobu condition were used under negative ion-mode. conducted to synthesize these aforementioned Results: Separation of the S and R enantiomers was prodrugs. achieved for 5-, 8-, 11-, 15-, 16-, 17- and 19-HETEs, Results: Nitrobenzyl bromides proved to be the most but not 9-, 12- and 18-HETEs. Single-ion- effective alkylating agents for synthesizing hypoxia- monitoring of HETE-DATAANs were performed at activated SN-38. 4-Nitro and 2-nitro substituted m/z=535, and the linearity range extended between benzyl ethers of SN-38 have been synthesized, with 0.0625 and 2 µg/mL. HETE-DATAANs were stable yields of 51% and 74%, respectively. at least 4 weeks, and the intraday and interday Conclusion: Two nitrobenzyl alkylated SN-38s have precision and accuracy did not exceed 20% of %CV been synthesized successfully, to be tested as and %error, respectively, at the lower limit of hypoxia-activated prodrugs. quantitation. Also, 2 specific transitions were determined for each HETE-DATAAN that allowed the simultaneous stereospecific determination of 88. Development and Validation of a Reverse- individual HETE by multiple-reaction-monitoring. phase Liquid Chromatography Mass Conclusion: The new method is sensitive, reliable Spectrometry Method for the Stereoselective and compatible with the readily available liquid Determination of Hydroxyeicosatetraenoic chromatography systems that would facilitate Acids correlation studies on HETEs levels with disease state, promoting the discovery of new disease 1 1 Ahmed A. El-Sherbeni , Dion R. Brocks , Randy M. markers and novel drug targets. 2 1 Whittal and Ayman O.S. El-Kadi . Support: This work was funded by CIHR to AOSE, 1 Faculty of Pharmacy and Pharmaceutical Sciences, and AAE is the recipient of Alberta Innovates- 2 University of Alberta; Department of Chemistry, Health Solutions studentship. Faculty of Science, University of Alberta, Edmonton, Canada 89. Targeting the Oncogenic FOXM1 Purpose: Hydroxyeicosatetraenoic acids (HETEs) Transcription Factor in Cancer Treatment are constitutively produced in vivo by cytochrome P450-mediated hydroxylation of arachidonic acid. Asya Elshaikh and Carlos Velazquez. HETEs are 11 different regioisomers, 10 of them Faculty of Pharmacy and Pharmaceutical Science, have a chiral center, leading to 20 different S/R University of Alberta, Edmonton, Alberta, Canada enantiomers. Despite the reported stereoselectivity in the formation and in the biological activities of Purpose: Genome-wide gene expression proﬁling of HETEs, almost all previous studies were confined to human cancers has consistently identiﬁed the the determination of HETEs regioisomers, Forkhead box M1 (FOXM1) transcription factor as overlooking HETEs enantiomers. This is because the one of the most commonly activated genes in cancer previously-reported separation of HETEs cells. Also, abnormal activation of the FOXM1 gene enantiomers needs normal-phase chromatography is regarded as one of the hallmarks of chemoresistant

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cancer cells. Accumulating evidence suggests that approaches, molecular docking and dynamics (MD) targeted FOXM1 inhibition could be a promising simulations of drug-M2 interactions supported our strategy to treat many types of cancer. The aim of design hypothesis. In-house medicinal chemistry this project is to validate the FOXM1 transcription was carried out to synthesize derivatives. We factor as a drug target. investigated M2 activity by co-transfecting cells Method: We recently carried out a series of with plasmids encoding GFP and M2(S31/N31) and molecular modeling protocols in which we have recording pH-dependent currents by whole-cell determined the binding energies of 3,323 FDA- patch clamp electrophysiology. Antiviral activities approved drugs within the FOXM1/DNA binding were tested in a viral cytopathic assay. domain and we have identified six promising virtual Results: The potency of the most active compound reference drugs with significant binding affinities. In (SM111) in inhibiting WT influenza virus is the lab, the MTT assay has been carried out on comparable with that of amantadine (EC50 = 5.2 µM HepG-2 cell line to test the ability of the drugs to vs. 0.4 µM) which correlates well with the inhibit cancer cell proliferation, followed by RT- electrophysiology assay. On the other hand, SM146 PCR to measure the expression of FOXM1 and its shows dual inhibitory effect against both A/M2 WT downstream target genes: MMP2, KIF20A, ccnb1, and the mutant (S31N) with an IC50 of 0.6 µM and ccnd1, NEK2, VEGFa, SOD2, and BcL2. 4.4 uM respectively. SM146 also inhibited viral Results: Three of the drugs gave promising primary replication in viral cytopathic assay with an EC50 of results including: thiostrepton (control) IC50 = 2.293 39.6 µM and 18.2 µM against InfluA virus bearing uM, troglitazone IC50 = 17.76 uM, and gliquidone S31 and N31 respectively. IC50 = 61.82 uM. As well, they found to inhibit the Conclusion: We described a novel class of expression of FOXM1 and its downstream target acylguanidines that inhibit InfluA virus and M2 ion genes except MMP2 gene for thiostrepton and channel and are stable and tolerated in vivo. SM146 gliquidone. is the first and the most potent non-adamantane dual Conclusion: We found that the drug troglitazone, a inhibitor (S31 and N31) of InfluA virus and M2 ion known anti-diabetic agent, exerts strong binding channel. The potency of the lead molecule in both interactions in the FOXM1/DNA binding domain, electrophysiology and antiviral assays suggests making this molecule the best drug candidate to efficacy of this novel class of compounds which can inhibit the transcriptional activity of this oncogenic act as a basis for their further development as protein potential broad-spectrum antivirals in attempt to confront InfluA virus resistance.

90. Inhibition of Influenza A M2 Ion Channel by Novel, Non-cytotoxic Derivatives of 91. Determination of Polyphenolic Content and Hexamethylene Amiloride Antioxidant Capacity of Wild Newfoundland Berries Pouria H. Jalily, Jodene Eldstrom, Ian Tietjen, David Fedida Scott Unruh1, Michelle Debnath-Canning1, Poorva Department of Anesthesiology, Pharmacology, and Vyas2, Andrei Igamberdiev2 and John Weber1 Therapeutics, University of British Columbia, School of Pharmacy1 and Department of Biology2, Vancouver, British Columbia, Canada Memorial University of Newfoundland

Purpose: M2 is a virally-encoded ion channel that is Purpose: Antioxidants including polyphenols and required for influenza replication. Licensed therapies ascorbate found in Vaccinium berry species (e.g. such as amantadine and rimantadine, which are blueberries and lingonberries) have been reported to potent M2 inhibitors, are no longer effective due to have a positive effect on health, including brain widespread drug resistance. Almost all adamantane- aging. We have conducted a detailed chemical resistant viruses encode a S31N mutation within M2. analysis of compounds detected in Vaccinium Thus, compounds that target both WT and S31N species. We also performed a pilot study aimed at mutant are highly desired. We describe novel HMA- determining the extent to which polyphenols can derived compounds that inhibit WT and S31N M2 enter the brain when included in the diet. and viruses with minimal cytotoxicity. Method: Berries were collected from several Methods: Conventional medicinal chemistry locations in the St. John’s, Newfoundland area, and

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extracts were produced using a variety of solvents. often require a pharmacological intervention. Here Biochemical assays were performed to determine the we examined for the functional changes in drug phenolic content of extracts, including total metabolism caused by obesity, using the phenolics, tannins, flavonoids, and antioxidant antiarrhythmic drug amiodarone as a test substrate. capacity. Comparisons of ascorbic acid levels Methods: Livers were harvested from male between wild lingonberries and blueberries were Sprague–Dawley rats given for 14 weeks either also determined. To quantify and identify major a.) control diet with water, b.) Normal rodent chow anthocyanins, High-Performance Liquid and high fructose corn syrup water (HFCS), c.) 45% Chromatography Mass-Spectroscopy (HPLC-MS) high fat diet (HFD) chow with water, or d.) a analysis was performed on extracts. Mice were also combination of HFCS and HFD. After the isolation administered blueberry extracts by oral gavage once of hepatic microsomal proteins, amiodarone HCl a day for two weeks, at which time they were killed was incubated with the microsomes. The incubation and the brains were harvested. mixture consisted of different concentrations of AM, Results: The biochemical assays showed that leaves 2 mg/mL microsomal protein, 1 mM NADPH and 5 have a significantly higher content of polyphenols mM MgCl2 in 0.5 M phosphate buffer (pH=7.4) in a and ascorbate in comparison to fruits. Blueberries total volume of 0.5 ml. The incubation was also had a higher level of ascorbate present in both performed over the linear range of the formation of the leaf and fruit extract in comparison to wild the AM metabolite desethylamiodarone (DEA) for lingonberries. Using HPLC-MS, more anthocyanins 10min at 37C. Reactions were stopped by the were identified and detected in blueberry fruit addition of cold acetonitrile followed by HPLC extracts than leaves, but the anthocyanins in leaf analysis for AM and DEA. The Michaelis-Menten extracts were present in higher quantity. We were equation was used to determine Vmax and Km. unable to detect polyphenols such as anthocyanins in Results: There was a significant reduction in Vmax the brain tissue of mice. in the HFD group and increase in Km in HFCS Conclusion: Leaves have a significantly higher level group compared to lean controls. In addition, a of antioxidants compared to the fruits, suggesting significant reduction of CLint in all groups potential use as nutraceutical products. Although we compared to controls. were unable to detect anthocyanins in brain, this was Conclusion: Obesity can decrease the functional likely due to technical issues and work is still activity of liver drug metabolizing enzymes. If ongoing in order to determine the extent to which translated to humans this finding might require polyphenols can enter the brain. adjustment of the amiodarone dose in obesity. Acknowledgement: Scott Unruh is the recipient of 2016 GSK/CSPS National Undergraduate Student Group Vmax, km, μM CLint, Research Program Award. pmol/mg uL/mg/min protein/min Control 150±28.7 59.8±21.6 2.65±0.67 HFD 73.1±6.10a 44.3±15.3 1.78±0.53d Pharmacokinetics & HFCS 137±21.9 119±12.9b 1.15±0.16d Pharmacodynamics HFD- 136±61.4 101±50.5c 1.51±0.50d HFCS

Comparison were made using one way ANOVA. a 92. The Impact of Diet-induced Obesity on the different from control, HFCS, and HFD-HFCS b Metabolism of Amiodarone to (p<0.050); different from control and HFD c Desethylamiodarone (p<0.050); different from HFD (p<0.050); d Different from control. Marwa Al-Agili, Ali Abdussalam, Dion R. Brocks. Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB

Purpose: Obesity is widespread throughout the world, and is associated with comorbidities that

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93. Effect of Diet Induced Obesity on obesity causes a decrease in the functional activity of Dronedarone Microsomal Metabolism in the liver microsomes. Rat

Yousef Bin Jardan, Ali Abdussalam, Dion R. Brocks 94. Using Population PBPK Modelling to Explore Faculty of Pharmacy and Pharmaceutical Sciences, Variability in Trastuzumab University of Alberta, Edmonton, AB Pharmacokinetics

Purpose: To explore the effect of diet induced Paul Malik, Colin Phipps, Andrea Edginton obesity on the metabolism of dronedarone as a School of Pharmacy, University of Waterloo substrate. Methods: Livers were harvested from male Purpose: The project seeks to explore the effects of Sprague–Dawley rats (n=6) exposed to the following anthropometric diversity on the pharmacokinetics of diets for 14 weeks: a.) normal rodent chow and trastuzumab using population PBPK modelling and water (controls), b.) 45% high fat (HFD) diet and virtual population generation. The hypothesis is that water, c.) normal rodent chow and high fructose corn the interindividual variability in trastuzumab syrup water (HFCS), and d.) both HFD and HFCS. pharmacokinetics can be accounted for by diversity The microsomal proteins were isolated and exposed in anthropometric parameters (height, body mass to dronedarone. The incubation mixture consisted of and organ flow rates). different concentrations of dronedarone, 0.5 mg/mL Methods: A comprehensive in silico whole-body microsomal protein, 1 mM NADPH and 5 mM PBPK model was developed for trastuzumab MgCl2 in 0.5 M phosphate buffer (pH=7.4) in a a according to a platform model and optimized using total volume of 0.3 mL. Incubation was performed standard modelling methods. A virtual population over the linear range for the dronedarone metabolite was generated with diversity in height, body mass (desbutyldronedarone) formation for 10 min at 37C. and organ flow rates that matched the mean and HPLC was used to determine the concentration of standard deviation in anthropometric parameters analytes. Substrate inhibition and Michaelis-Menten from the sample population in an experimental pharmacokinetic trial (Wisman et al.). All other equations were used to determine Vmax and km. Results: parameters were held constant between individuals. The virtual human parameters were used as inputs for the model and the simulated variability was Group Vmax , Km, μM CLint, pmol/mg µL/min/ compared with the observed variability in the protein/min mg protein experimental pharmacokinetic trial (Wisman et al.). Control 210.8±3.4 6.7±2.5 33.6±9.6 Results: The solid blue shading indicates the HFD 95.4±17.4† 96.2±41.5† 1.1±0.23† standard deviation of the plasma concentration Data are expressed as mean ± SD. values for the virtual population. The black lines mark the standard deviation seen in the trial by

Wisman et al. The formation of desbutyldronedarone in Controls followed a pattern consistent with substrate inhibition/inactivation (the velocity curve reached the maximum and then descended as the substrate concentration increased further). There were significant difference (p<0.05) in Vmax, Km and CLint values in HFD group compared to Controls (Student’s t-test). In the HFCS and combined HFD- HFCS groups there were linear increases in desbutyldronedarone formation vs. concentration profiles over the span of concentrations studied, preventing an estimation of Vmax or km. However, it Conclusion: Anthropometric diversity is responsible was clear that the formation rates were reduced for only a small component of the interindividual compared to controls based on the concentration vs. variability seen in trastuzumab pharmacokinetics. rate plots. Further research with this model will be conducted Conclusion: This data showed that diet induced to identify the influence of other parameters on

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variability. The model and conclusions for PTX and 0.8-1.07h for RPX in rats. Compared to trastuzumab can be generalized to all monoclonal PTX- or RPX-micelles, composite PMs produced antibody drug products. higher AUC for both PTX (13.56±1.80µg*h/ml) and Acknowledgement: Paul Malik is the recipient of RPX (40.36±4.09µg*h/ml). Composite PMs also 2016 GSK/CSPS National Undergraduate Student increased Cmax (63.31±19.05µg/ml for PTX and Research Program Award. 135.97±19.96µg/ml for RPX) and reduced Vss (0.62±0.32L/kg for PTX and 0.12±0.01L/kg for RPX). 95. Anti-cancer Stem Cell Effect and Conclusion: Composite PMs significantly reduced Pharmacokinetics of Composite Polymeric viability and stemness of CSCs in HCC-1954 cancer Micelles of Reparixin and Paclitaxel cells. Pharmacokinetic study in rats indicated enhancement of AUC and Cmax for both drugs by Sarandeep Malhi, Samaa Alrushaid, Neal Davies, composite PMs. Xiaochen Gu College of Pharmacy, University of Manitoba, Winnipeg, Canada 96. Optimization and Development of Novel Topical Intestinal Agonists of the Bile Acid Purpose: Breast cancer stem cells (CSCs) were Receptor TGR5 for Treatment of Diabetes reportedly resistant to conventional therapies, and Mellitus and Associated Metabolic Diseases their proportion increases after treatment. Gene profiling of CSCs revealed overexpression of Manuel Lasalle1, Anne Tailleux2, Nathalie CXCR1, a receptor for cytokine IL-8. We have Hennuyer2, Loïc Belloy2, Catherine Piveteau1, developed composite polymeric micelles (PMs) of Adrien Herledan1, Vanessa Hoguet1, Florence reparixin (RPX, a potent CXCR1 antagonist) and Leroux1, Hélène Gras-Masse1, Bart Staels2, Benoit paclitaxel (PTX) to target both CSCs (CXCR1+ and Deprez1, Julie Charton1. ALDHFLUOR+) and bulk tumor cells respectively, 1Inserm U1177, Univ. Lille, Institut Pasteur de Lille. and tested their anti-CSCs effects in vitro and Faculté de pharmacie, Lille, France; 2Inserm U1011, pharmacokinetics in vivo. Univ. Lille, Institut Pasteur de Lille, Lille, France Methods: Poly(ethylene glycol)-block-poly(D,L- lactic acid) PMs were prepared by lyophilization Purpose: TGR5 is a ubiquitous GPCR sensitive to technique. In vitro cytotoxicity was evaluated in bile acids. Its activation in intestinal enteroendocrine sorted (CXCR1+ and ALDEFLUOR+) and unsorted L cells increases GLP-1 secretion, an incretin mammosphere HCC-1954 breast cancer cells. hormone known to have a good potential in the Stemness reduction efficacy was evaluated using treatment of diabetes mellitus. Nevertheless, recent limited dilution assay (LDA) and mammosphere in vivo experiments have shown that activation of formation assay (FMA). Pharmacokinetic study was TGR5 by systemic agonists could induce on-target performed in rats intravenously administered with unwanted effects such as swelling of the gallbladder, PMs. Plasma drug concentrations were analyzed or cardiovascular dysfunctions. We have using validated LC-MS/MS assay. Pharmacokinetic hypothesized that selective activation of TGR5 in parameters were calculated using non- the intestine combined with limited systemic compartmental model by WinNonlin® software. exposure would lead to beneficial effects on glucose Results: Significant decrease in viability was homeostasis, while preventing unwanted effects. observed in unsorted cells treated with PTX and Methods: Using the SAR obtained on our TGR5 composite PMs. In sorted CXCR1+ cell RPX-PMs agonists, structural elements were introduced to induced significant viability loss, while PTX- prevent systemic exposure. Such analogs were micelles induced lower cytotoxicity. Composite PMs evaluated in vitro to assess their potency on TGR5. efficiently decreased viability in both unsorted and Solubility, LogD, microsomal stability and Caco2 sorted cells. Flow cytometric analysis indicated 3- permeability were also determined. In vivo and 5-fold decrease in CXCR1+ and ALDHFLUOR+ experiments were then carried out on mice to study CSCs respectively. The increase confidence interval the pharmacokinetic and pharmacological profiles of of 1 CSCs per 250 cells confirmed the decreased one of the best compound. stemness of cultures treatment with composite PMs. Results: Introduction of a sulfonate group on an Plasma elimination half-life ranged 0.94-1.06h for adequate position through a convergent 10 steps

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synthesis lead to compound 2. It displayed proof of principle that it was possible to trigger an promising improvements in physico-chemical and enhanced GLP-1 secretion (6.1 fold) with no ADME properties compared to its unmodified significant gallbladder swelling. analog compound 1 (Log D : 0.8 vs 3.5 ; Caco2 Conclusion: Our strategy lead to compound 2, a permeability : 0.03 10-6 cm/s vs 4.4 10-6 cm/s), while potent agonist of TGR5 with a fine-tuned PK profile, remaining as potent (mEC50 : 0.5 nM vs 0.8 nM). translating into an optimized pharmacological Oral administration of 2 in mice lead to a 10,000 behavior in vivo. This compound will now be further fold difference between intestinal and plasmatic evaluated in animal models of diabetes mellitus. concentrations (Cmax int. = 900 µM vs Cmax pl = 0.1 Note: Part of this work was already presented at the µM). Unexpectedly, gallbladder concentrations were 18th SCI/RSC Medicinal Chemistry Symposium in found to be 100 fold higher than in the plasma (Cmax Cambridge, UK (Sunday 13 - Wednesday 16 GB = 10 µM). Dose-dependent and time-dependent September 2015) evaluation of pharmacological effects established the

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AFPC POSTER PRESENTATIONS - JUNE 2, 2016

AFPC - 33 Tamiz J. Kanji, Tony T. Seet The Impact of Standardized Patients on First Year Students in an Entry-to-practice PharmD Program at the University of British Columbia AFPC - 34 I fan Kuo, Inderpaul Ruprai, Shawn Parliamentarians in the Classroom: Learning Ethics and Bugden Pharmacy Practice Issues Through Debates AFPC - 35 Shawn Bugden, I fan Kuo Enhancing Quality by Using Instruction on Qualitative Methods as a Course Evaluation Tool AFPC - 36 Grace Frankel, Christopher New Skills Lab Component for Pharmacy Student: Louizos, I fan Kuo Ordering and Interpreting Laboratory Tests AFPC - 37 Vaughn T. Chauvin, Tamiz Kanji The Impact of Practical Skills Instruction and Application in Improving Student Confidence to Engage in Point of Care INR Monitoring and Management AFPC - 38 Annie Lee, Andrew Tolmie, Designing, Testing and Implementing a Standard Mahmoud Suleiman, Diana Assessment Tool for Field-Based Pharmacy Training Spizzirri, Stephanie Chiu, Henry Halapy AFPC - 39 Annie Lee, Thomas Huang, Danish Effectiveness of the Peer-to-Peer Mentoring Model for Tanwar, Certina Ho Transitioning from Classroom to Professional Practice AFPC - 40 Christopher Louizos, Casey L. Implementing the Informatics for Pharmacy Students E- Sayre, Bruce D. Audit, Grace E. resource into the University of Manitoba, College of Frankel, Robert D. Renaud Pharmacy AFPC - 41 Glenda P. MacDonald, Peter S. Brain Gain: Evaluation of Prior Learning Assessment and Loewen, Patricia Gerber, Madeleine Recognition (PLAR) in a Canadian Doctor of Pharmacy H.P. Lee, James P. McCormack Program AFPC - 42 Rachel Magarinos-Torres, Milton Profile of the Hospital Pharmacists Workers in Rio de D. Lucas-Filho, Monique A. Brito Janeiro, Brazil AFPC - 43 Shannon Del Bigio, Stephanie Perceptions of Teamwork and Interprofessional Education Mulhall, Yvonne Shevchuk, Holly in Undergraduate Pharmacy Students Mansell AFPC - 44 Janice L. Moshenko, Jimi Galvao, Career Communications Workshops for Pharmacy Angela Pau Students: Development, Implementation and Evaluation AFPC - 45 Janice L. Moshenko, Larry Leung, Impact of a Communication Session for Pharmacy Jason Min, Fong Chan, David Students: Preparation for IPE Collaboration Massaro, Parkash Ragsdale AFPC - 46 Lauren F. Ferruccio, Doret Cheng, Providing Academic Support to Students in Experiential Cindy Natsheh Education (PASS-EE): A Survey of Canadian and American Faculties of Pharmacy AFPC - 48 George Pachev, Marion Pearson, Evaluating the Function and Impact of a Formative Simon Albon, Andrea Busse Assessment Program in the UBC E2P PharmD Program: First Term Insights AFPC - 49 Lisa McCarthy, Natalie Crown, Training Pharmacists to Become Personalized Medicine Beth A. Sproule, Micheline Experts Piquette-Miller, Daniel Mueller,Thomas Boyang Huang

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AFPC - 50 Robert D. Renaud, Sheryl A. Predictive Validity of Admission Tools on Student Zelenitsky, John A. Pugsley, Shawn Performance in the Pharmacy Program and on the C. Bugden National Licensing Examination AFPC - 51 Cynthia L. Richard, Alana H. Establishment of a 2nd Year Midpoint Assessment to Rigby, Andrea N. Edginton Identify Students for Remediation AFPC - 52 Tony Seet, Katherine Seto, Andrea The Implementation of New Assessment Strategies in a Busse, George Pachev Medication Management Module within an Introductory Course in an Entry-to-Practice PharmD Program AFPC - 53 Katherine Seto, Brian B. Rodrigues Development and Implementation of a Foundations of Pharmacy Course in an Entry-to-Practice PharmD Program AFPC - 54 Paulo Tchen, Leo Leung, Frances Bridging the Gap from the Classroom to the Institutional Simpson, Angela Kim-Sing, Practice Site: Evaluation of an Online Transition Module Marion Pearson for Student Pharmacists AFPC - 55 Neelam Dhaliwal, Frances Developing Online Learning Modules for Pharmacy Simpson, Ashley Shaw, Angela Practice Educators Kim-Sing AFPC - 56 Neelam Dhaliwal, Frances Preliminary Evaluation of Online Practice Educator Simpson, Iona Berger, Angela Development Modules Kim-Sing AFPC - 57 Harvinder Singh, Hélène Jolin, Development and Evaluation of a Hierarchical Model of Tracy Zhang, Tim Veregin Teaching for a Hospital Pharmacy Direct Patient Care Rotation AFPC - 58 Andrew Tolmie, Nancy M. Waite, Communities of Practice: An Innovation in Experiential Emily P. Milne Education AFPC - 59 Amanda J.S. Condon, Fiona M. The Process of Developing an Entry to Practice Faculty of Jensen, Laura L. MacDonald, Dana Health Sciences Interprofessional Collaborative Care A. Turcotte, Pam F. Wener Longitudinal Curriculum AFPC - 60 Anne Marie Whelan, Dianne Cox Doctor of Pharmacy Program Development: Stakeholder Survey, College of Pharmacy, Dalhousie University AFPC - 61 Anne Marie Whelan, Dianne Cox Former/Current Student Feedback Regarding the Progress Exam at the College of Pharmacy, Dalhousie University AFPC - 62 Kerry Wilbur, Emily Black Describing Student Performance; A Comparison Between Clinical Preceptors across Cultural Contexts AFPC - 63 Kerry Wilbur, Kyle Wilby Pharmacy Student Evaluations in Landscapes of Changing Educational Outcomes and Expectations

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. Index

Bin Jardan, Yousef, 117 A Blenke, Erik Oude, 78 Bolton, James, 70 Abdulla, Dalya, 70 Borchers, Christoph, 7, 56, 58 Abdussalam, Ali, 116, 117 Borchers, Christoph H., 7, 12, 56, 58 Acosta, Crystal, 65 Bosc, Damien, 69 Adomat, Hans, 98 Brocks, Dion R., 90, 114, 116, 117 Agu, Remigius U., 88 Brooks, Donald, 83, 111 Akahoshi, Tomohiko, 96 Bryan, Stirling, 6, 12, 51 Akinwumi, Bolanle C., 65 Burczynski, Frank J., 63 Al Lawati, Hanan, 82 Burt, Helen M., 83, 111 Al Nakouzi, Nader, 98 Buser-Doepner, Carolyn, 2, 8, 18 Al Zahabi, Khaled, 74 Al-Agili, Marwa, 116 C Alam, Camille, 66 Al-Bayati, Karam, 102 Campbell, Scott B., 110 Alcorn, Jane, 64, 66, 71 Campioli, Enrico, 69 Al-Dulaymi, Mays, 64 Casini, Angela, 87 Alessi-Severini, Silvia, 70, 91 Cawthray, Jacqueline, 104, 105 Algabbass, Kholud, 86 Cecic, Ivana, 5, 10, 41 Ali, Farzad, 2, 8, 23 Chadha, Renu, 77 Allen, Kevin, 86 Chan, Nicky, 73 Almousa, Ahmed, 71 Chang, Hilary, 67 Almutairi, Adah, 5, 11, 45 Charton, Julie, 118 Alrushaid, Samaa, 87, 88, 118 Chateau, Dan, 70 Amsden, Brian, 7, 13, 59, 60 Chen, Gang, 50, 97 An, So Young, 73 Chen, K., 76 Anantha, M., 76 Chen, Kuan, 108 Anderson, Hope D., 65 Chen, Michael, 7, 12, 56, 57 Andre, Christophe, 98 Chen, Yufei, 87, 107 Awrey, Shannon, 98 Cheng, Pui Chi, 71 Azarmi, Shirzad, 106 Cherkasov, Artem, 98 Chiang, Linus, 68 Chokshi, Killol S, 67 B Chung, Haeun, 86 Babcook, John, 2, 8, 20 Clark, Peter G. K., 69 Backstrom, I., 76 Clarke, Ryan, 68 Badea, Ildiko, 64 Collier, Abby, 3, 9, 27, 89 Badv, Maryam, 81 Cooper, Dave, 104 Bagal, Dhanashri, 7, 12, 56 Corbin, Ian, 76 Bally, M.B., 76 Corey Nislow, 1 Bandiera, Stelvio M., 86 Coyle, Doug, 4, 10, 38, 39 Bansback, Nick, 100 Cullis, Pieter, 2, 20, 78 Barakji, Marwan, 67 Barralet, Jake, 69 D Baum, Lindsay, 70 Bear, Christine, 97 Dalisson, Benjamin, 69 Bell, Madelaine, 6, 12, 53, 100, 101 Daneshtalab, Noriko, 67 Belloy, Loïc, 118 Daugaard, Mads, 98 Belmont, Lisa, 5, 10, 42 Davies, Neal M., 63, 87, 88, 118 Bendayan, Reina, 66 De Silva, Franklyn, 66 Bernard, Florian, 106 De Vera, Mary, 3, 9, 33 Bhatti, Masood, 84 Debnath-Canning, Michelle, 68, 115 Billinsky, Jennifer, 71 Del Rosario, Teresa, 84

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Deprez, Benoit, 118 Harrison, Mark, 6, 12, 51, 100 Di, Yunyun, 71 Hartmann, Susanne, 98 Doré, Jules, 67 Hashizume, Makoto, 96 Dragojlovic, Nick, 4, 10, 39, 96 Hassona, Mohamed D.H., 98 Dranitsaris, George, 71 Hengge, Regine, 98 Drolet, B., 93 Hennink, Wim E., 78 Droubi, Dounia, 78, 103 Hennuyer, Nathalie, 118 Herledan, Adrien, 118 E Heuck, Gesine, 77, 103, 104 Hill-Taylor, Barbara, 99 Edginton, Andrea, 3, 9, 27, 28, 117, 121 Ho, Emmanuel A., 74, 80, 81, 87, 102, 107 Edwards, K., 76 Hoare, Todd R., 5, 45, 81, 110 Ehling, Josef, 78 Hoguet, Vanessa, 118 Eldstrom, Jodene, 115 Hoogenboom, Richard, 5, 11, 45 El-Kadi, Ayman O.S., 114 Hope, Michael, 2, 8, 21 Elshaikh, Asya, 114 Horne, Fred, 4, 10, 37 El-Sherbeni, Ahmed A., 114 Høtoft Michaelsen, Maria, 72 Endrenyi, Laszlo, 3, 9, 30 Hung, Maurita, 97 Enns, Murray W., 70 Hynynen, Kullervo, 4, 9, 34

F I Fang, Yuhua, 85 Igamberdiev, Andrei, 68, 115 Feagan, Brian, 71 Ikeda, Tetsuo, 96 Fedida, David, 115 Ip, Shell, 77, 103, 104 Fens, Marcel H.A.M., 78 Fonge, Humphrey, 64 J Fourie, Anne, 2, 8, 22 Fowke, Keith R., 107 Jahan, Sheikh Tasnim, 72 Fowler, Sharyle, 71 Jalily, Pouria H., 115 Fumakia, Miral, 81, 107 Jamali, Fakhreddin, 3, 5, 11, 30, 47, 82 Janek, Katharina, 98 Jazani, Arman Moini, 73 G Jian, Hui, 94 Gallant, Sarah, 88 Jimenez, Celine, 74 Garg, Shyam, 77, 78, 103, 104 Jimenez, Vincent, 80 Gauthier, Marc, 5, 11, 45, 46 Jones, Jennifer, 71 Gélinas, C., 93 Ghasemi, N, 108 K Ghosh, Supratim, 105 Gleave, Martin, 83, 111 Kane, Anil, 108 Gong, Yuewen, 63, 76 Kaur, Kamaljit, 82 Gras-Masse, Hélène, 118 Kawano, Takahito, 96 Groothuis, Geny, 87 Kebir, Hania, 106 Gu, Jijin, 102 Kizhakkedathu, Jayachandran, 83, 111 Gu, Xiaochen, 118 Klassen, Tara L., 89, 91, 95 Günther, Sebastian, 98 Klein, Agnes, 3, 9, 31 Guo, Linghong, 110 Knibbe, Catherijne, 3, 9, 28 Gupta, Nidhi, 63 Ko, Na Re, 73 Koehn, Cheryl, 6, 12, 52 Kolathuru, Shyam Sundar, 88 H Kovacic, Suzana, 69 Haddadi, Azita, 72, 91 Kritharis, Thanos, 103 Hadjistavropoulos, Thomas, 71 Krol, Ed, 86, 105 Hajdu, Istvan, 64 Hall, Dennis, 109 L Halyk, Chris, 2, 8, 25 Hamano, Nobuhito, 96 Lai, Raymond, 63, 109 Hamilton, C. Michael, 97 Lakowski, Ted, 84, 87, 90, 93 Haneef, Jamshed, 77 Lallous, Nada, 98

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Lammers, Twan, 78 Mohammed-Saeid, Waleed, 64 Lamont, Matthew, 67 Mohan, Sankar, 98 Lasalle, Manuel, 118 Morin, Helene, 98 Lavasanifar, Afsaneh, 63, 82, 83, 108, 109 Moskalev, Igor, 83 Lawn, Sam, 98 Mu, Huiling, 72 Le, Canh Tien, 113 Mugabe, Clement, 6, 11, 50, 83, 111 Le, Tyson, 63 Muirhead, Ben, 110 Leaver, Tim, 77, 78, 103, 104 Müllertz, Anette, 72 Leblanc, Eric, 98 Munuganti, Ravi S.N., 98 Leclair, Grégoire, 106 Murata, Masaharu, 96 Lécuyer, Marc André, 106 Lee, Amy, 4, 10, 34, 35, 36 Lee, Danielle I., 65 N Leong, Amanda, 100 Nagabushnam, Kalyanam, 87 Leong, Christine, 70 Nakata, Ryosuke, 96 Leroux, Florence, 118 Narahara, Sayoko, 96 Leung, A., 76 Neuman, Manuela G, 101 Li, Jason, 108 Nie, Yao, 70 Li, Lily Yi, 108, 112 Nislow, Corey, 1, 3, 5, 11, 26, 41, 42, 43, 44 Li, Marc, 66 Novaes, Júlia T., 87 Li, Shyh-Dar, 1, 4, 9, 34, 75, 79, 80, 102 Li, Yuping, 78 Liang, Dinghua, 113 O Liggins, Richard, 83, 111 Oh, Jung Kwon (John), 73 Lillico, Ryan, 84, 87, 93 Orvig, Chris, 87, 104 Liu, Jie, 78 Osorio-de-Castro, Claudia Garcia Serpa, 97 Liu, Luna, 7, 12, 57 Ou, Kevin, 104 Lockard, Ray, 104 Ouellet, Eric, 78, 103, 104 Loebenberg, Raimar, 5, 47, 94, 106, 110 Lopez-Correa, Catalina, 5 Lory, Jacob, 98 P Lun, Eric , 4, 10, 38 Padilla, Fernanda, 80 Lynd, Larry , 1, 3, 4, 33, 37, 96, 97 Page, Jonathan, 5, 10, 40 Lynd, Larry D. , 1, 3, 4, 33, 37, 96, 97 Paiva, Igor, 82, 83 Papadopoulos, Vassilios, 69 M Parr, Mike, 83, 111 Patoine, D., 93 Ma, Mark, 100, 103 Petriew, Sarah, 86 MacCallum, Caroline, 5, 10, 40 Phipps, Colin, 117 Magarinos-Torres, Rachel, 97, 120 Piao, Jing Shu, 96 Main, David, 2, 8, 23 Pieters, Ebel H.E., 78 Majeed, Muhammed, 87 Pilote, S., 93 Makowsky, Mark, 100 Pimstone, Simon, 1 Malhi, Sarandeep, 118 Piveteau, Catherine, 118 Malhotra, A., 76 Pompeo, Alysa, 100 Malik, Paul, 117, 118 Poon, David, 6, 11, 49 Mansell, Kerry, 71 Poteet, Joshua, 105 Marques, Paulo Eduardo Coutinho, 97 Prat, Alexandre, 106 Marshall, Keara, 103 Prior, Heather J., 70 Martinez, Stephanie E., 88 Mateescu, Mircea Alexandru, 113 May, Jonathan P., 75 R McCabe, Chris , 4 Rades, Thomas, 72 McCabe, Christopher , 37 Ramsay, Euan, 77, 78, 103, 104 McEachern, Ernest , 2, 8, 19 Rehan, Sara, 99, 100 Michel, Deborah , 64 Rennie, Paul S., 98 Midha, Ankur , 98 Riches, Zoe, 89 Minuk, Gerald Y. , 76 Rieder, Meghanne, 104, 105 Mitchell, Deborah , 105 Rigby, Heather, 99 Mohammed, Munawar , 104, 105 Roa, Wilson, 110

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Rosebrock, Adam, 7, 12, 55 Theek, Benjamin, 78 Roshan-Moniri, Mani, 98 Theivendra, Nalliah, 84 Ross, Colin, 5, 11, 43 Thomas, Anitha, 77, 78, 103, 104 Roullin, V. Gaëlle, 106 Thompson, John, 68 Roy, Aniruddha, 80 Thompson, Kara, 99 Thorpe, Lilian, 71 Tietjen, Ian, 115 S Tirunellai, Krishnan, 3, 9, 31 Sadatsafavi, Mohsen, 6, 12, 52 Tomlinson Guns, Emma, 98 Saifan, Loay, 74 Torchilin, Vladimir, 6, 11, 48 Sakharkar, Meena, 66 Toutah, Krimo, 97 Sallam, AlSayed, 74 Tranmer, Geoffrey, 85, 113 Saqr, Asma, 109 Traore, Yannick, 7, 13, 59, 80, 107 Sareen, Jitender, 70 Traore, Yannick L., 80, 107 Sassene, Philip, 72 Sayre, Casey L., 87, 88, 120 U Schiffelers, Raymond M., 78 Schimmer, Aaron, 3, 9, 26 Unruh, Scott, 68, 115, 116 Schlosser, Josephine, 98 Seira, Oscar, 78 Selvaganapathy, P. Ravi, 110 V Serra, Diego, 98 Vakili, Mohammad Reza, 82, 108, 109 Shao, Zongjun, 65 van der Meel, Roy, 5, 11, 45, 78 Sharma, Karun, 66 van der Zee, Margot, 87 Sheardown, Heather, 7, 13, 59, 110 van Nostrum, Cornelus F., 78 Sherrington, Robin, 2, 8, 19 Velazquez, Carlos, 114 Shi, Yang, 78 Verdelet, Tristan, 109 Shire, Zahra, 109 Vezenkov, Lubomir, 69 Sidhu, Suki, 103 Viirre, Russ, 97 Simard, C., 93 Viveky, Navita, 71 Singh, Jagbir, 77, 103, 104 Vogl, A. Wayne, 86 Singh, Kriti, 98 Vyas, Poorva, 68, 115 Singleton, Scott, 6, 12, 54 Sketris, Ingrid, 99 Smith, Alexander D., 91, 95 W So, Alan, 83, 111 Walsby, Charles, 68 Soleymani Abyaneh, Hoda, 63 Wang, Yu Tian, 78 Soudy, Rania, 82 Wasan, Ellen, 104, 105 Spreckelmeyer, Sarah, 87 Wasan, Kishor M., 64, 72, 104 Staels, Bart, 118 Weber, John, 67, 68, 115 Stesco, Nicholas, 93 Weekes, David, 104 Stoeber, Boris, 7, 13, 60 Wehbe, Moe, 76 Storm, Gert, 78 Weinfeld, Michael, 109 Storr, Tim, 68 Whiting, Susan, 71 Stürup, Stefan, 87 Whittal, Randy, 114 Sun, Tongbing, 73 Wild, Andre, 77, 78, 103, 104 Sussman, Django, 6, 11, 49 Wu, Xiao Yu (Shirley), 7, 13, 61, 108, 112 Sutherland, Mathew, 68 Syeda, Jaweria, 104, 105 Szeitz, András, 89 X Xiao, Shujun, 95 T Tailleux, Anne, 118 Y Tang, Wei-Hsin (Sophia) , 79 Yamazaki, Takeshi, 98 Tang, Wei-Lun , 75, 79 Yang, Jian, 95 Taylor, James , 2, 8, 21, 77, 78, 103, 104 Yang, Jiaqi, 76 Tedin, Karsten , 98 Yang, Jun, 110 Terry, Paul , 2, 8, 24 Yang, Shilin, 94 Tetzlaff, Wolfram , 78 Yang, Sidi, 74, 107 Tharmarajah, Grace, 78

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Yang, Xiaolei, 64 Z Yang, Yang, 80 Yearley, Jennifer, 2, 8, 22 Zhang, Chen, 68 Yeung, Pollen K., 88 Zhang, Huaifa, 69 Yoo, Shannon, 110 Zhang, Rui Xue, 4, 10, 36, 112 Younes, Husam M., 74 Zhao, Yucheng (Rita), 102 Young, Robert N., 1, 2, 6, 11, 22, 48, 50, 69, 97, 98 Zheng, Gang, 4, 9, 35 Yuan, Zhipeng, 110 Zier, Kira-Isabel, 106 Zuo, Jieyu, 94 Zuo, Zhengyun, 94

126s | CSPS/CC-CRS Conference 2016, Vancouver, BC, Canada