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(Dfmo) & Etoposide Loaded Nanocarriers for the Tr DEVELOPMENT AND EVALUATION OF POLYMERIC HYBRID α- DIFLUOROMETHYLORNITHINE (DFMO) & ETOPOSIDE LOADED NANOCARRIERS FOR THE TREATMENT OF NEUROBLASTOMA A DISSERTATION SUBMITTED TO THE GRADUATE DIVISION OF THE UNIVERSITY OF HAWAI’I AT HILO IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY IN PHARMACEUTICAL SCIENCES AUGUST 2016 By MICAH DAVID KEALAKA’I GLASGOW Dissertation Committee: Mahavir B. Chougule, Primary Adviser Kenneth R. Morris, Co-Adviser Dana-Lynn Koomoa-Lange Mazen Hamad Cheryl Ramos Ghee Tan Keywords: Neuroblastoma, DFMO, Etoposide, Combination chemotherapy, Drug delivery, Multifunctional nanocarriers 1 | Page © 2016, MICAH DAVID KEALAKA’I GLASGOW 2 | Page DEDICATION I’d like to dedicate my dissertation to my family, who have always supported me through all my endeavors. My mother and father, Lillian & James Glasgow, my sisters, Renae & Melissa, my brothers, Shawn & Ikaika and my nephews, Nakana & Kaulana Glasgow. They have always been my foundation in life and the reason I continue to excel in any task I undertake. My degree wouldn’t have been possible without their undying sacrifice and love throughout the years. I’d also like to dedicate my work to my Aunty Connie Law and Aunty Alvernia Inamine who lost their battle with cancer but continue to watch over me from above. I will always remember their words of encouragement and generous hearts forever [xoxo]. Love you all! 3 | Page ACKNOWLEDGEMENTS I’d like to thank the numerous people I had the great opportunity to work with during my Ph.D. tenure. A special thanks to my colleagues and lab members; Mrs. Marites Calibuso-Salazar, Mr. Nishant Gandhi, Dr. Susanne Youngren-Ortiz, Dr. Rongbing Yang, and Dr. Laura Espana Serrano for their knowledge and input throughout my dissertation. An enourmous amount of gratitude goes to my co-adviser, Dr. Kenneth Morris, for encouraging me to apply to the Ph.D. in Pharmaceutical Sciences program at the Daniel K. Inouye College of Pharmacy (DKICP), UHH. Dr. Morris unknowingly is also my role-model and I feel very fortunate to have had the opportunity to work alongside him at DKICP. Many thanks also to Dr. Dana-Lynn Koomoa-Lange for sacrificing her time and energy to mentor me throughout my project. Also, her heavy involvement with the community allowed me to share the knowledge I’ve obtained to the next generation of scientists. Herself, along with Dr. Morris, have also financially supported me throughout my Ph.D. tenure and I am forever grateful for their generosity and kindness. A special thanks to my primary adviser, Dr. Mahavir Chougule, whom I’m sure wanted to strangle me at times but kept on believing I could get my project done. He allowed me to work on a project I had no knowledge of and therefore it allowed me to grow as a researcher. We may have gotten into several, actually many, disagreements but in the end I am truly grateful for his time and dedication to seeing my project through, thank you very much. Thank you to my remaining committee members; Dr. Mazen Hamad, whose equipment I always managed to break, and Dr. Cheryl Ramos whose radiant smile will brighten anyone’s day. To all of my committee members, please enjoy the honor of reading my 300+ page dissertation, you’re very welcome. I’d like to thank the numerous scholarship and grant agencies for providing financial support during my Ph.D. tenure. I’d first like to acknowledge the National Science Foundation – Engineering Resource Center on Structured Organic Particulate Solids (NSF-ERC-SOP) for stipend support and support of minorities in the higher education field. Thank you to these numerous scholarship agencies for their support in obtaining my doctorate in the pharmaceutical sciences degree; Kamehameha Schools Na Ho’okama a Pauahi Scholarship, Hawai’i Community Foundation, Dr. Hans and Clara Zimmerman Fund, Ke Ola Mau Scholarship, Rosemary & Nellie Ebrie Fund, Shelley M Williams RPh Scholarship Fund, Walter Francis and Mary Dillingham Frear Scholarship, ALEX travel award, University of Hawaii at Hilo Alumni Scholarship, Na Ho’okahua Award (Department of Education), George & Lucille Cushnie Scholarship Fund, Liko A’e Native Hawaiian Leadership Scholarship, University of Hawai’i at Hilo 2014 Community 4 | Page Spirit Award, Kukui Malama Scholarship Award. I would also like to thank the University of Hawai’i at Hilo - Daniel K. Inouye College of Pharmacy for providing a tuition waiver and a year of stipend support. 5 | Page ABSTRACT Neuroblastoma (NB) is the most common extra-cranial solid cancer in childhood and infancy with patients having an average age of 17 months. Most are diagnosed with advanced stage NB when tumor progression is aggressive, making treatment of NB even more difficult. Up to 45% of patients are in the high-risk category with MYCN gene amplification being observed. The FDA-approved drug difluoromethylornithine (DFMO) exhibits anticancer activity against MYCN- amplified NB cells. DFMO is a suicide inhibitor of ornithine decarboxylase (ODC), a rate-limiting enzyme in the biosynthesis of polyamines. ODC gene expression is directly activated by MYCN suggesting that MYCN amplification is connected to high ODC expression. ODC expression produces high polyamine levels that contribute to the malignant phenotype and maintenance of NB tumorgenesis. This MYCN-ODC connection suggests that ODC may be a suitable new target for the treatment of NB with the administration DFMO. Etoposide, a topoisomerase inhibitor is often used in front-line therapy in the treatment of NB. The use of DFMO/Etoposide in vivo is currently limited due to the short half-lives (fast elimination/clearance) of both drugs which may explain why antitumor in vivo were not synergistic as observed in vitro. iRGD peptide-conjugated PEGylated polymeric hybrid nanocarriers loaded with synergistically acting DFMO and Etoposide drugs (iRGD-PEG-HNC-D-E) were characterized at 81±7nm in size, +12±2.5mV in zeta potential with a mean polydispersity index 0f 0.354±0.03. The developed nanocarriers had a 10 and 6-fold decrease in initial drug concentrations, DFMO and Etoposide respectively, with similar efficacy as compared to free drugs alone against various NB cell-lines over a 72h period. The current formulation shows stability suspended in phosphate buffer saline (PBS) 7.4 over 6 days. iRGD-PEG-HNC-D-E formulations can be modified (polymer: polymer ratio) to alter drug release profiles with the developed formula having a 90% release of both drugs after 72h in PBS 5.4 and 7.4 containing glutathione. 6 | Page TABLE OF CONTENTS DEDICATION ACKNOWLEDGEMENTS ABSTRACT LIST OF TABLES LIST OF FIGURES LIST OF ABBREVIATIONS AND SYMBOLS FLOW DIAGRAM OF PROPOSED THESIS WORK 1. INTRODUCTION 1.1 Cancer and Nanotechnologies 1.2 Brief overview of Neuroblastoma 1.3 Cancer Therapy 1.4 Mechanisms of drug resistance 1.5 Combination chemotherapies 1.6 Small molecule drugs of interest: α-Difluoromethylornithine (DFMO) and Etoposide 1.7 Synergistic effects of DFMO and Etoposide in vitro and in vivo 1.8 Combination chemotherapy nanocarriers against multi-drug resistant (MDR) cancer 1.9 Overview of iRGD Peptide as a potential Tumor Target for Neuroblastoma treatment 2. HYPOTHESIS, OBJECTIVES, AND RATIONALE 3. LITERATURE REVIEW 3.1 CURRENT NANOCARRIERS AS MULTIFUNCTIONAL DRUG DELIVERY SYSTEMS 3.2 Liposomes 3.3 Polymeric micelles 3.4 Poly-(lactic-co-glycolic acid)-based nanocarriers 3.5 Mesoporous silica based nanocarriers (MSNPs) 3.6 Polymer-drug nano-conjugates 3.7 Dendrimers based nanocarriers 3.8 Miscellaneous multifunctional nanocarriers 4. CURRENT PROGNOSIS AND THERAPEUTIC TREATMENTS FOR NEUROBLASTOMA 4.1 INTRODUCTION 4.2 DIAGNOSTIC STUDIES AND TESTS 4.3 PROGNOSTIC FACTORS 4.3.1 Histology 4.3.2 MYCN Oncogene 7 | Page 4.3.3 Tumor Cell Ploidy 4.3.4 Chromosome Abnormalities 4.3.5 Neurotrophins and Neurotrophin Receptors 4.4 RISK GROUP STRATIFICATION SYSTEM 4.5 RISK-BASED TREATMENT 4.5.1 Low-Risk Disease 4.5.2 Intermediate-Risk Disease 4.5.3 High-Risk Disease 4.6 Treatment of Spinal Cord Compression 4.7 Treatment of Opsoclonus/Myoclonus Syndrome 4.8 NEW THERAPEUTIC AGENTS 4.8.1 Cytotoxic Agents 4.8.2 Retinoids 4.8.3 Immunotherapy 4.8.4 Radioiodinated mIBG 4.8.5 Antiangiogenic Therapy 4.8.6 Late Effects of Therapy 4.9 Summary 5. CURRENT NANOCARRIER DELIVERY SYSTEMS FOR NEUROBLASTOMA 6. TARGETED MULTIFUNCTIONAL NANOCARRIERS IN COMBINATION CHEMOTHERAPEUTICS 6.1 Antibodies and antibody fragment based targeted nanocarriers 6.2 Peptide-based targeted nanocarriers 6.3 Small molecule based targeted nanocarriers 6.4 Aptamer-based targeted nanocarriers 6.5 Miscellaneous targeted approaches 7. iRGD PEPTIDE FOR CANCER THERAPY 7.1 Antagonists (Non-Antibody) of αvβ3 7.2 RGD-Targeted Delivery of Therapy 7.2.1 Chemotherapy 7.2.2 Peptides and Proteins 7.2.3 Nucleic Acids 7.2.4 Radionuclides 7.2.5 Theranostics 8 | Page 7.2.6 iRGD Cyclic Penetrating Peptide 7.3 Summary of RGD Peptide as a Potential Ligand to Target Tumors 8. THERNOSTICS MULTIFUNCTIONAL NANOCARRIERS FOR CHEMOTHERAPY AND IMAGING 9. THERNOSTICS SUMMARY 10. QUANTIFICATION OF α-DIFLUOROMETHYLORNITHINE (DFMO) AND ETOPOSIDE USING HIGH PERFORMANCE LIQUID CHROMATOGRAPHY (HPLC) AND PLATE-READER 10.1.1 Derivatization of DFMO using TNBSA (2, 4, 6-trinitrobenzene sulfonic acid) assay for UV- detection 10.1.2 Quantification of DFMO derivative using Biotek plate-reader 10.1.3 Quantification of DFMO derivative using HPLC 10.1.4 Detection and Quantification of Etoposide using HPLC 10.1.5 Simultaneous Detection and Quantification of DFMO derivative and Etoposide using HPLC 11. IN VITRO CYTOTOXICITY STUDIES OF DFMO AND ETOPOSIDE ALONE 11.1.1 Introduction to MTT and MTS cell proliferation assays 11.1.2 MTT 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide Cell Proliferation Assay 11.1.3 MTS (3-(4, 5-dimethylthiazoly-2yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H- tetrazolium) Cell Proliferation Assay 11.2 In vitro Dose-response durves of DFMO and Etoposide drugs alone 11.3 In vitro DFMO and Etoposide drug combination studies 11.4 Determination of Synergistic, Additive or Antagonistic Effect on Neuroblastoma cell-lines 12.
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