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Nanomedicines and Combination Therapy of Doxorubicin and Olaparib for Treatment of Ovarian Cancer

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Nanomedicines and Combination Therapy of Doxorubicin and Olaparib for Treatment of Ovarian Cancer Nanomedicines and Combination Therapy of Doxorubicin and Olaparib for Treatment of Ovarian Cancer by Sina Eetezadi A thesis submitted in conformity with the requirements for the degree of Doctor of Philosophy Department of Pharmaceutical Sciences University of Toronto © Copyright by Sina Eetezadi 2016 Nanomedicines and Combination Therapy of Doxorubicin and Olaparib for Treatment of Ovarian Cancer Sina Eetezadi Doctor of Philosophy Department of Pharmaceutical Sciences University of Toronto 2016 Abstract Ovarian cancer is the fourth leading cause of death in women of developed countries, with dismal survival improvements achieved in the past three decades. Specifically, current chemotherapy strategies for second-line treatment of relapsed ovarian cancer are unable to effectively treat recurrent disease. This thesis aims to improve the therapeutic outcome associated with recurrent ovarian cancer by (1) creating a 3D cell screening method as an in vitro model of the disease (2) developing a nanomedicine of doxorubicin (DOX) that is more efficacious than PEGylated liposomal doxorubicin (PLD / Doxil®) and (3) evaluating additional strategies to enhance treatment efficacy such as mild hyperthermia (MHT) and combination therapy with inhibitors of the poly(ADP-ribose) polymerase enzyme family (PARP). Overall, this work demonstrates the use of 3D multicellular tumor spheroids (MCTS) as an in vitro drug testing platform which more closely reflects the clinical presentation of recurrent ovarian cancer relative to traditional monolayer cultures. With the use of this technology, it was found that tissue penetration of drug is not only an issue for large tumors, but also for invisible, microscopic lesions that result from metastasis or remain following cytoreductive surgery. A novel block-copolymer micelle formulation for DOX was developed and fulfilled the goal of ii controlling drug release while enhancing intratumoral distribution and MCTS bioavailability of DOX, which resulted in a significant improvement in growth inhibition, relative to PLD. MHT appeared to enhance drug accumulation in MCTS in the short term, but not after 48 h of drug treatment. Drug combination studies of DOX together with the PARP inhibitor, olaparib (OLP, Lynparza®) were conducted in 2D monolayers and 3D MCTS. In these studies, the effectiveness of the DOX:OLP combination therapy in monolayers and MCTS was found to be ratio dependent such that equimolar ratios resulted in an additive effect, while a greater level of synergy was observed with more extreme ratios. The synergistic effect observed bears promise for future evaluation in vivo which warrants an appropriate delivery method to ensure that the determined molar ratios of both drugs accumulate at the tumor as such, despite differences in the pharmacokinetic profile of each drug, respectively. iii Dedication Dr. Ebrahim Eetezadi Mortui Viventes Obligant. iv Acknowledgements Good science is always the result of good teamwork and this thesis is no exception. First and foremost I would like to thank Prof. Christine Allen for her continuous support over the past 5 years, especially during the rather unconventional endeavors I embarked on. Christine has been a role model with an unparalleled work ethic and has taught me important lessons in perseverance and leadership. I am especially grateful for the responsibilities she entrusted me with, which helped me to grow and develop my own leadership skills. Second, I would like to express my special gratitude to Dr. Payam Zahedi and Dr. Raquel De Souza. Payam gave me the most valuable advice at the beginning and during this PhD project. Raquel was an incredible support and enabled to the most productive time during the last 6 months of this doctorate. Furthermore, I would like to thank the Drs. Andrew Mikhail and Changhai Lu who had the patience to train me in the lab and made substantial contributions to the third and fourth chapter of this thesis. I would also like to thank Sandra Ekdawi for her relentless strive for perfection, which made the second chapter what it had become. I would have never come even close to this result without her. Mohammad Ali Amini, Mike Dunne, Sohyoung Her, Karen Lam and Rida Mourtada have been the greatest friends inside and outside the lab. Thank you for all the scientific and more importantly non-scientific talks. I would also like to thank my students Rodrigo Lessa Cataldi, Mirugashini Vythilingam and Larissa Da Gama, who all did outstanding experimental work. v I would like to acknowledge Dr. Andreas Rummelt, Prof. Cornelia Halin Winter, Prof. Jean- Christophe Leroux, Prof. Beat Ernst, Prof. Rob Macgregor, Prof. Heiko Heerklotz, Prof. David Hedley and Prof. Raymond Reilly for their direct or indirect support at different stages of this dissertation. This work would not have been possible without my parents, who fostered my curiosity during my early years, taught me to never accept the world as it is and had to be extremely patient, while their son was for years somewhere on the other side of the Atlantic studying something of which neither duration nor outcome was ever really apparent. Last but not least I would like to thank my wife Shokoufeh for being there for me from start to finish with all the up and downs along the way. She has been the light and warmth when science puts you in a cold, dark tunnel where time and speed is lost. Nihil tam difficile est, quin quaerendo investigari possit. vi Table of Contents Abstract .................................................................................................................................... 2 Dedication ................................................................................................................................ 4 Acknowledgements ................................................................................................................ 5 Table of Contents ................................................................................................................... 7 List of Tables ......................................................................................................................... 12 List of Figures ........................................................................................................................ 13 List of Abbreviations............................................................................................................. 19 ........................................................................................................................... 1 1.1. Introduction ............................................................................................................... 2 1.1.1. Ovarian Cancer Treatment in Clinical Practice ................................................ 2 1.1.2. The Role of PEGylated Liposomal Doxorubicin in Ovarian Cancer .............. 4 1.1.3. Targeting DNA Repair in Ovarian Cancer ......................................................... 6 1.2. Rationale .................................................................................................................. 10 1.3. Hypothesis .............................................................................................................. 13 1.4. Overview of Thesis Chapters ............................................................................... 14 1.5. References .............................................................................................................. 16 ......................................................................................................................... 22 2.1. Abstract ................................................................................................................... 23 2.2. Introduction ............................................................................................................. 24 2.3. Biology vs. Block Copolymer Micelles ............................................................... 28 2.3.1. First line of defense: the blood compartment ............................................... 28 2.3.2. Second line of defense: tumor extravasation and accumulation .............. 34 2.3.3. Third line of defense, and the Achilles’ heel of nanomedicines: tumor penetration and tumor drug bioavailability .................................................................... 43 2.4. Translatability: best practices and lessons learned ........................................ 52 2.4.1. Towards clinically relevant nanoformulations............................................... 53 vii 2.4.2. The management of heterogeneity at the pre-clinical and clinical levels 57 2.5. Conclusions ............................................................................................................ 67 2.6. Acknowledgements ............................................................................................... 68 2.7. References .............................................................................................................. 69 ......................................................................................................................... 80 3.1. Abstract ................................................................................................................... 81 3.2. Introduction ............................................................................................................. 82 3.3. Materials and Methods ......................................................................................... 85 3.3.1.
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