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A Novel Protein Drug, Suprachoroidal Delivery, and Protein Sustained Release Systems for Choroidal Neovascularization

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A Novel Protein Drug, Suprachoroidal Delivery, and Protein Sustained Release Systems for Choroidal Neovascularization A NOVEL PROTEIN DRUG, SUPRACHOROIDAL DELIVERY, AND PROTEIN SUSTAINED RELEASE SYSTEMS FOR CHOROIDAL NEOVASCULARIZATION by PUNEET TYAGI M. Pharm., Hamdard University, India 2003 B. Pharm, CCS University, India 1997 A thesis submitted to the Faculty of the Graduate School of the University of Colorado in partial fulfillment of the requirements for the degree of Doctor of Philosophy Pharmaceutical Sciences Program 2013 This thesis for Doctor of Philosophy degree by Puneet Tyagi has been approved for the Pharmaceutical Sciences Program by Robert I. Scheinman, Chair Uday B. Kompella, Advisor Krishna Mallela Ravi Mahalingam Jeffrey Olson Date: 12/05/13 ii Tyagi, Puneet. (Ph.D., Pharmaceutical Sciences) A Novel Protein Drug, Suprachoroidal Delivery, and Protein Sustained Release Systems for Choroidal Neovascularization Thesis directed by Professor Uday B. Kompella. ABSTRACT Ocular posterior segment diseases such as age related macular degeneration are leading causes of blindness worldwide. Identification of various new disease targets have led to the development of inhibitors of vascular endothelial growth factor such as bevacizumab, ranibizumab, and aflibercept. A critical barrier for the translation of any new promising drug intended for the posterior segment diseases is drug delivery to the back of the eye. Topical eye drop, which is the most convenient dosage form, typically does not achieve therapeutically effective drug levels in the retina. Systemic modes of administration are associated with high drug exposure to other organs, and hence, systemic toxicity. Frequent intravitreal injections can lead to retinal detachment and endophthalmitis. The objective of this research was to create a novel transferrin-tumstatin fusion protein based on an endogenous antiangiogenic tumstatin and evaluate its efficacy in vitro and in vivo and compare it to bevacizumab and tumstatin. Following design, expression, and efficacy assessment, pharmacokinetics and safety of transferrin-tumstatin was assessed in rabbits. Suprachoroidal route of delivery was validated in rats and the delivery of sodium fluorescein by this route was compared to subconjunctival and iii intravitreal routes. A delivery system for sustained in vivo delivery of bevacizumab following suprachoroidal administration was developed. Transferrin-tumstatin was superior to bevacizumab and tumstatin in inhibiting choroid endothelial cell proliferation, tube formation, and migration. The in vivo efficacy of transferrin-tumstatin was superior to bevacizumab and tumstatin in inhibiting CNV in a rat model. Transferrin-tumstatin was eliminated from the vitreous humor with a half life of about 2 days and was safe following intravitreal injection in rabbits. Further, suprachoroidal injections are feasible in rats and the extent and rate of delivery of sodium fluorescein to choroid-retina was the highest following suprachoroidal delivery, when compared to intravitreal and posterior subconjunctival injections. A light-activated in situ forming gel sustained the delivery of bevacizumab after suprachoroidal dosing. The form and content of this abstract are approved. I recommend its publication. Approved: Uday B. Kompella iv This thesis is dedicated to my wife and son for their constant support and encouragement. v ACKNOWLEDGEMENTS First and foremost, I would like to express my deepest regards and gratitude to Dr. Uday B. Kompella for providing me the opportunity and support to work under his supervision. I am really thankful to him for always assisting me to his fullest extent under all circumstances and for his immense generosity and expertise as a teacher and for his patience and support over the years that I have spent in his laboratory. Under his guidance not only I could advance myself scientifically, I could also improve my writing and oral presentation skills by a tremendous amount. This thesis was possible only because of valuable insights provided by him as an accomplished scientist and advisor. I will forever cherish his guidance and look forward to his advice. I am also grateful to other members of my thesis committee members – Dr. Robert Scheinman, Dr. Krishna Mallela, Dr. Ravi Mahalingam, and Dr. Jeffrey Olson for their extremely valuable recommendations, suggestions, encouragement and insightful comments. It has been a privilege for me to have committee members as scientific guides. I am forever grateful to them. I am also thankful to all my past and present colleagues and friends in the Department of Pharmaceutical Sciences – Ruchit Trivedi, Shelley Durazo, Shreya Kulkarni, Sunil Vooturi, Arun Upadhyay, Rajendra Kadam, Swita R. Singh, Rinku Baid, Jiban Jyoti, Jiban Anand, Vidhya Rao, Gajanan Jadhav, Ashish Thakur, Namdev Shelke, Chandrasekar Durairaj, and Sneha Sundaram, for their joyous company and insightful comments. I am especially thankful to Ruchit Trivedi, Rajendra Kadam, and Swita Singh for being such wonderful friends and for being there at times of need. vi I would also like to acknowledge the financial support from school of Pharmacy and from National Institute of Health. Finally, I would like to acknowledge my parents for always believing me in all my decisions in life including the pursuit of this program. They are my greatest source of inspiration and strength. Last but not least I would like to thank my wife and son for their support, patience, understanding, and immense faith on me. vii TABLE OF CONTENTS CHAPTER I. STATEMENT OF PROBLEM ........................................................................... 1 Introduction .....................................................................................................1 Specific aims for the thesis ..............................................................................8 II. INTRODUCTION .............................................................................................11 Age related macular degeneration .................................................................11 Basic definition of AMD ...............................................................................12 Choroidal neovascularization ........................................................................14 Role of pro-angiogenic factors in CNV ........................................................ 15 Therapeutic strategies for CNV .....................................................................17 Drawbacks of current therapeutic strategies of CNV ....................................19 Endogenous inhibitors of CNV .....................................................................21 Inhibition of angiogenesis by tumstatin .........................................................23 Transferrin-tumstatin, a novel fusion protein for CNV .................................24 Current techniques for drug delivery to the posterior region of the eye ............................................................................................25 Suprachoroidal delivery for posterior region of the eye ................................27 Sustained delivery systems for posterior region of the eye ...........................29 Sustained release systems for proteins ..........................................................31 viii III. A NOVEL TUMSTATIN FUSION PROTEIN FOR CHOROIDAL NEOVASCULARIZATION ...........................................33 Abstract ......................................................................................................33 Introduction ................................................................................................34 Materials and methods ................................................................................37 Results ........................................................................................................45 Discussion ..................................................................................................56 Conclusions ................................................................................................60 IV. PHARMACOKINETICS AND SAFETY OF A NOVEL TRANSFERRIN-TUMSTATIN FUSION PROTEIN IN RABBITS .............. 61 Abstract ......................................................................................................61 Introduction ................................................................................................62 Materials and methods ................................................................................64 Results ........................................................................................................68 Discussion ..................................................................................................75 Conclusions ................................................................................................76 V. COMPARISON OF SUPRACHOROIDAL DRUG DELIVERY WITH SUBCONJUNCTIVAL AND INTRAVITREAL ROUTES USING NONINVASIVE FLUOROPHOTOMETRY .....................................77 Abstract ......................................................................................................77 Introduction ................................................................................................78 Materials and methods ................................................................................82 Results ........................................................................................................85 Discussion ..................................................................................................95 Conclusions ..............................................................................................101
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