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PREFORMULATION AND BIOLOGICAL EVALUATIONS FOR THE INTRAVAGINAL DELIVERY OF GRIFFITHSIN FOR HIV PREVENTION by Lindsay Ferguson Kramzer Doctor of Pharmacy, University of Pittsburgh, 2009 Submitted to the Graduate Faculty of School of Pharmacy in partial fulfillment of the requirements for the degree of Doctor of Philosophy University of Pittsburgh 2015 UNIVERSITY OF PITTSBURGH SCHOOL OF PHARMACY This dissertation was presented by Lindsay Ferguson Kramzer It was defended on March 23, 2015 and approved by Sharon L. Hillier, PhD, Department of Obstetrics & Gynecology, School of Medicine Bernard J. Moncla, PhD, Department of Obstetrics & Gynecology, School of Medicine Song Li, MD, PhD, Departmental of Pharmaceutical Sciences, School of Pharmacy Raman Venkataramanan, PhD, Department of Pharmaceutical Sciences, School of Pharmacy Dissertation Advisor: Lisa C. Rohan, PhD, Department of Pharmaceutical Sciences, School of Pharmacy ii PREFORMULATION AND BIOLOGICAL EVALUATIONS FOR THE INTRAVAGINAL DELIVERY OF GRIFFITHSIN FOR HIV PREVENTION Lindsay Ferguson Kramzer, PharmD University of Pittsburgh, 2015 Copyright © by Lindsay Ferguson Kramzer 2015 iii PREFORMULATION AND BIOLOGICAL EVALUATIONS FOR THE INTRAVAGINAL DELIVERY OF GRIFFITHSIN FOR HIV PREVENTION Lindsay F. Kramzer, PharmD University of Pittsburgh, 2015 HIV/AIDS persists as a global health concern, with the overwhelming majority of infections caused by sexual transmission. The lack of effective prevention modalities for women has prompted research of novel approaches to prevent disease spread. One such approach includes vaginal microbicides. The work presented within this dissertation project contributes significantly to the vaginal microbicide field, focusing on preformulation assessments, stability in the biological environment, and drug targeting of the biopharmaceutical microbicide candidate Griffithsin (GRFT). We hypothesized that GRFT will undergo physical and chemical instabilities that will affect successful formulation and vaginal delivery of this microbicide candidate. We further hypothesized that GRFT will undergo binding interactions within cervicovaginal secretions that will negatively impacting GRFT-gp120 binding and that GRFT will not be able to inhibit HIV binding to the DC-SIGN receptor and transfer to CD4 cells because GRFT will not permeate cervical tissue. Identification of degradation pathways for GRFT was conducted by performing preformulation experiments under selected conditions of temperature, light, shear, ionic strength, and oxidation. Analytical methods included HPLC, CD, UV-spectroscopy, ELISA, and SDS- PAGE. GRFT chemical modifications, including intact mass analyses and peptide sequencing, were evaluated in the presence of hydrogen peroxide and human cervicovaginal secretions. The iv effects of human cervicovaginal secretions on GRFT-gp120 binding was also assessed with ELISA. Tissue permeability and localization of GRFT was evaluated using excised human ectocervical tissue. Major findings from this dissertation indicate that: (1) GRFT is prone to oxidation, by both hydrogen peroxide exposure and human cervicovaginal secretion exposure; (2) Methionine at position 78 in the amino acid sequence of GRFT is oxidized; (3) GRFT-gp120 binding is inhibited in human cervicovaginal secretions containing normal microflora, but not in secretions with BV; and (4) GRFT does not permeate deep into or through human cervical tissue, but does adheres to the superficial epithelial tissue. Overall, this dissertation has created more knowledge about a drug candidate in the microbicide field and will guide further development of GRFT. Further, the methodologies implemented throughout this dissertation can be used or adapted as part of a strategy to preclinically evaluate other vaginal microbicide candidates. v TABLE OF CONTENTS PREFACE ................................................................................................................................. XVI 1.0 INTRODUCTION ........................................................................................................ 1 1.1 HIV/AIDS – GLOBAL HEALTH PROBLEM ................................................. 1 1.1.1 HIV – Statistics ................................................................................................ 1 1.1.2 HIV Pathogenesis ............................................................................................. 3 1.1.3 HIV – The Basics ............................................................................................. 4 1.2 HIV PREVENTION WITH ANTIRETROVIRALS ..................................... 10 1.2.1 HIV PrEP – In Development ........................................................................ 12 1.3 SEXUAL (MUCOSAL) TRANSMISSION OF HIV – MALE-TO-FEMALE TRANSMISSION ............................................................................................................... 16 1.4 HUMAN VAGINAL ANATOMY AND PHYSIOLOGY .............................. 19 1.4.1 Cervicovaginal Secretions ............................................................................. 22 1.5 VAGINAL DRUG DELIVERY ........................................................................ 25 1.6 VAGINAL PREP FOR HIV PREVENTION IN FEMALES........................ 27 1.6.1 Microbicide Dosage Formulation Considerations ...................................... 27 1.6.2 Vaginal Microbicides – Past, Present, and Future ..................................... 30 1.7 IDEAL VAGINAL MICROBICIDE ............................................................... 40 1.8 GRIFFITHSIN – A MUCOSAL PREP CANDIDATE .................................. 42 vi 1.9 HYPOTHESES AND SPECIFIC AIMS ......................................................... 45 2.0 PREFORMULATION EVALUATIONS OF GRIFFITHSIN............................... 48 2.1 INTRODUCTION ............................................................................................. 48 2.2 MATERIALS AND METHODS ...................................................................... 50 2.2.1 High Performance Liquid Chromatography .............................................. 50 2.2.2 UV-Spectroscopy ........................................................................................... 51 2.2.3 Circular Dichroism ........................................................................................ 51 2.2.4 SDS-PAGE ..................................................................................................... 51 2.2.5 gp120 Binding ELISA ................................................................................... 52 2.2.6 Physical and Chemical Stability Assessments ............................................. 53 2.2.7 Biologically-Relevant Assessments ............................................................... 55 2.2.8 Statistical Analyses ........................................................................................ 56 2.3 RESULTS ........................................................................................................... 56 2.3.1 Physical and Chemical Stability ................................................................... 56 2.3.2 Biologically-Relevant Assessments ............................................................... 64 2.4 DISCUSSION AND CONCLUSIONS ............................................................. 70 3.0 GRIFFITHSIN OXIDATION ................................................................................... 79 3.1 INTRODUCTION ............................................................................................. 79 3.2 MATERIALS AND METHODS ...................................................................... 80 3.2.1 Hydrogen Peroxide Exposure ....................................................................... 81 3.2.2 Human Cervicovaginal Lavage Exposure ................................................... 81 3.2.3 High Performance Liquid Chromatography .............................................. 82 3.2.4 Mass Spectrometry – Intact Mass ................................................................ 82 vii 3.2.5 Mass Spectrometry – Peptide Sequencing ................................................... 83 3.2.6 SDS-PAGE of GRFT and Oxidative Products............................................ 84 3.2.7 gp120 Binding of GRFT and Oxidative Products....................................... 84 3.3 RESULTS ........................................................................................................... 85 3.3.1 Hydrogen Peroxide and CVL Exposure ...................................................... 85 3.3.2 Mass Spectrometry – Intact Mass ................................................................ 86 3.3.3 Mass Spectrometry – Peptide Sequencing ................................................... 91 3.3.4 SDS-PAGE of GRFT and Oxidative Products............................................ 92 3.3.5 gp120 Binding of GRFT and Oxidative Products....................................... 93 3.4 DISCUSSION AND CONCLUSIONS ............................................................. 94 4.0 EVALUATION OF THE EFFECT OF HUMAN CERVICOVAGINAL SECRETIONS ON GRIFFITHSIN BINDING TO GP120 .................................................... 98 4.1 INTRODUCTION ............................................................................................. 98 4.1.1 Human Cervical Mucus ................................................................................ 98 4.1.2 Bacterial Vaginosis .....................................................................................
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