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Hypotonic Delivery of Drugs and Drug-Loaded Nanoparticles to the Gastrointestinal Tract

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Hypotonic Delivery of Drugs and Drug-Loaded Nanoparticles to the Gastrointestinal Tract HYPOTONIC DELIVERY OF DRUGS AND DRUG-LOADED NANOPARTICLES TO THE GASTROINTESTINAL TRACT By Katharina Maisel A dissertation submitted to Johns Hopkins University in conformity with the requirements for the degree of Doctor of Philosophy Baltimore, Maryland December, 2014 © 2014 Katharina Maisel All Rights Reserved ABSTRACT Innovative gastrointestinal (GI) drug delivery vehicles such as mucus penetrating nanoparticles (MPP) and fluid-absorption inducing (hypotonic) delivery vehicles have potential to improve therapeutic outcomes over conventional methods such as mucoadhesive particles (MAP) for GI diseases, including ulcerative colitis (UC) and HIV pre-exposure prophylaxis (PrEP). More than 80% of all drugs are absorbed via the GI tract for either systemic or local treatment. MAP delivered to the GI tract are thought to improve oral absorption or local targeting of difficult-to-deliver drug classes. Mucus is a continuously secreted barrier that effectively traps foreign particulates to protect the underlying epithelium. Rapid clearance of the most superficial luminal mucus layers in the GI tract may limit the effectiveness of MAP. Here, I test the current dogma of mucoadhesion by comparing MAP and MPP GI drug delivery via the oral and rectal routes. In addition I investigate the development of several vehicles including rectal enemas and gels for more effective delivery of nanocarriers or free drugs. First, I illustrate that MPP uniformly coat all surfaces of the GI epithelium, while MAP aggregated in mucus in the center of the lumen, far away from the absorptive epithelium, both in healthy mice and mice with UC. In the mouse colorectum, MPP penetrated into mucus in the deeply in-folded surfaces to evenly coat the entire epithelial surface. Moreover, in UC mice, MPP were transported preferentially into the disrupted, ulcerated tissue. Next, I sought to design an effective enema vehicle for delivering MPP and non-mucoadhesive drugs locally to the colorectum. I found that MPP and free drug are only rapidly transported to the epithelial surface in sodium-based enemas, while potassium-based or isotonic and hypertonic (secretion-inducing) enemas cause ii heterogeneous surface coverage. Strongly hypertonic and hypotonic enemas cause rapid systemic drug absorption, while moderately hypotonic enemas improve local drug retention in tissue. Finally, I designed a microbicide-loaded MPP for PrEP, to be delivered in a novel osmotic thermogel. The MPP formulation evenly coated both the vaginal and colorectal epithelium and the hypotonically delivered thermogel effectively traps HIV, and significantly enhances drug and nanoparticle retention in the cervicovaginal tract. Advisor: Justin Hanes, PhD Thesis Committee: Justin Hanes, PhD; Richard Cone, PhD; Craig Hendrix, MD; Rangaramanujam Kannan, PhD; Youseph Yazdi, PhD; Laura Ensign, PhD iii ACKNOWLEDGMENTS I have had the opportunity to work with and be guided by many incredibly intelligent and wonderful people throughout graduate school. First, I would like to thank my advisor Dr. Justin Hanes for giving me the opportunity to work in his lab, allowing me the freedom to explore new research directions while making sure I kept the big picture in mind, always being open to giving advice personally or professionally, and teaching me about translating research to the clinic. I would like to thank my unofficial “co-advisor”, Dr. Richard Cone, for his always giving me his undivided attention, and guiding and supporting me professionally and personally in my research, professional development, and career decisions. I also need to thank my other collaborators and committee members: Dr. Craig Hendrix for giving me invaluable insights into the process of designing products that are translatable into humans; Dr. Rangaramanujam Kannan for supporting me in exploring new endeavors in the dendrimer realm in addition to always providing me with his wisdom on research and career decisions; Dr. Youseph Yazdi for sitting through many hours of research discussions and providing his insights on product development and big picture applications; and finally, Dr. Laura Ensign for teaching me everything I needed to know when I first joined the laboratory, for supporting me in venturing into new research directions (and convincing me not to get upset when things did not work out the way I intended), for welcoming me into her family and making Baltimore a place I could call home, and for being an inspiration in continuing onto a career in academia. I also need to thank many members of the Hanes Lab and Center for Nanomedicine. I’d like to especially thank those who came before me, who have taught iv me so much, and were always willing to give up some of their valuable time: Drs. Craig Schneider, Elizabeth Nance, Jung Soo Suk, Ben Schuster, Anthony Kim, Qingguo Xu, Tao Yu, Himat Patel, Manoj Mishra, Wojciech Lesniak, and Jie Fu. Next I’d like to thank those who have been in the lab with me throughout all these years, my classmates Jane Chisholm and Clark Zhang, who have been wonderful to bounce ideas off of, get encouragement and boost my confidence in next steps, and who have been all around fantastic friends. I look forward to seeing you both graduate soon! Next, I’d like to thank Shu Chattopadhyay for supporting me in my endeavors first as an undergraduate student, then as a master’s student, and now as a young PhD student. He has been invaluable to completing my work and I am so proud to see him grow into his new responsibilities as a doctoral candidate. I need to thank all the other current and former members of the Hanes and Cone lab “vag team” Terence Tse, Kunal Parikh, Thuy Hoang, Taarika Babu, Kevin DeLong, Derek Cerchione, Mihika Reddy, Megan Lamberti, Emily Toler, Stephen Chen, Veda Prasad, and Ashil Koranne. Joseph Vargas and Nicole Turner deserve special thanks for keeping everything running behind the scenes. I’d also like to thank Dr. Thomas Moench for his input on many of my research questions and struggles. Finally I’d like to thank all other members of the Center for their support, helpful attitude, and making the lab an all-around friendly, family-like environment. Most importantly I would like to thank my friends and family for their support and inspiration. Thanks to all my friends in and out of graduate school, in particular my best friend and former lab member Dr. Ben Tang for helping me through many crises, reading endless drafts of papers/letters/emails/abstracts, and always making me laugh even when I felt down. I’d like to thank my brother Simon and his wife Tanya for their v constant support and always welcoming me into their home in Boston. Ben, Simon, and Tanya formed my Boston support group that allowed me to escape into another city on numerous occasions throughout my PhD. Last but not least I’d like to thank my wonderful parents for everything they have done to get me here: taking the leap to move to the USA and deciding to stay here, supporting me emotionally, physically, intellectually, financially, and in every other possible way, and giving me the strength to follow my dreams. Without their inspiration, love, and guidance I would not have made it this far. Tausend Dank! vi TABLE OF CONTENTS ABSTRACT ........................................................................................................................ ii ACKNOWLEDGMENTS ................................................................................................. iv TABLE OF CONTENTS .................................................................................................. vii LIST OF TABLES ........................................................................................................... xiii LIST OF FIGURES .......................................................................................................... xv 1. INTRODUCTION AND SIGNIFICANCE................................................................. 1 2. BACKGROUND – CONSIDERATIONS FOR GASTROINTESTINAL DRUG DELIVERY......................................................................................................................... 3 2.1 Mucus ........................................................................................................................ 3 2.1.1 Stomach .............................................................................................................. 5 2.1.2 Small Intestine .................................................................................................... 5 2.1.3 Colon .................................................................................................................. 6 2.2 Food absorption and the mucus filter barrier ............................................................ 7 2.3 Fluid flow in the gastrointestinal tract ...................................................................... 8 2.3.1 Ion movement ..................................................................................................... 8 2.3.2 Water movement ............................................................................................... 10 2.3.3 Implications for drug delivery .......................................................................... 12 2.4 The mucus barrier, fluid absorption, and drug delivery using nanoparticles .......... 14 2.4.1 Surface characteristics that yield MPP ............................................................. 15 2.4.2 MPP for mucosal drug delivery ........................................................................ 16 2.4.3
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