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ABSTRACT FROMEN, CATHERINE ANN. Monodisperse, Uniformly ABSTRACT FROMEN, CATHERINE ANN. Monodisperse, Uniformly-Shaped Particles for Controlled Respiratory Vaccine Delivery. (Under the direction of Joseph M. DeSimone). The majority of the world’s most infectious diseases occur at the air-tissue interface called the mucosa, including HIV/AIDS, tuberculosis, measles, and bacterial or viral gut and respiratory infections. Despite this, vaccines have generally been developed for the systemic immune system and fail to provide protection at the mucosal site. Vaccine delivery directly to the lung mucosa could provide superior lung protection for many infectious diseases, such as TB or influenza, as well as systemic and therapeutic vaccines for diseases such as Dengue fever, asthma, or cancer. Specifically, precision engineered biomaterials are believed to offer tremendous opportunities for a new generation of vaccines. The goal of this approach is to leverage naturally occurring processes of the immune system to produce memory responses capable of rapidly destroy virulent pathogens without harmful exposure. Considerable knowledge of biomaterial properties and their interaction with the immune system of the lung is required for successful translation. The overall goal of this work was to fabricate and characterize nano- and micro- particles using the Particle Replication In Non-wetting Templates (PRINT) fabrication technique and optimize them as pulmonary vaccine carriers. The main objectives of this PhD research included (1) the development of a calibration-quality aerosol system using PRINT, the application of these calibration-quality aerosols to improve understanding of (2) shaped aerosols under flow and (3) their cellular fate in the lung, and (4) the application of this knowledge towards the development of a mucosal vaccine. We hypothesized that the precision particle control afforded by the PRINT technology could advance understanding of the role that particle features, such as size, shape, and surface charge, play on all aspects of pulmonary vaccine formulations. Particles were fabricated and optimized for delivery via the lung, exhibiting the first examples of monodisperse, non-spherical aerosols. The particle control afforded by the PRINT platform was also used to probe the biological function of key lung antigen presenting cells (APCs) in mice. We demonstrate for the first time the role of particle charge on airway APC association, finding that cationic particles were preferentially associated with lung dendritic cells, giving them a distinct advantage over anionic formulations in vaccine platforms. Subsequently, these cationic particles were found to increase production of both systemic and mucosal antibodies, demonstrating the importance of particle characteristics on pulmonary vaccination and the importance of surface charge in a T-cell dependent antibody response. This work contributes to the overall understanding of how parameters of precision engineered particles influence both pulmonary delivery and immune programing, towards the ultimate application of a translatable pulmonary vaccine formulation. © Copyright 2014 Catherine Ann Fromen All Rights Reserved Monodisperse, Uniformly-Shaped Particles for Controlled Respiratory Vaccine Delivery by Catherine Ann Fromen A dissertation submitted to the Graduate Faculty of North Carolina State University in partial fulfillment of the requirements for the degree of Doctor of Philosophy Chemical Engineering Raleigh, North Carolina 2014 APPROVED BY: _______________________________ ______________________________ Dr. Joseph M. DeSimone Dr. Michael Dickey Committee Chair ________________________________ ________________________________ Dr. Saad Khan Dr. Orlin Velev DEDICATION This dissertation is dedicated to my family for their continual support. ii BIOGRAPHY The author was born and raised in Medfield, MA to parents Greg and Debby Fromen. She entered the University of Rochester in Rochester, NY in 2005 and graduated with a B.S. in Chemical Engineering in 2009. During this time, she first participated in academic research under the direction of Steve Jacobs, Ken Marshall and Jerry Cox. She entered the PhD graduate program at North Carolina State University in the Department of Chemical and Biomolecular Engineering in the fall of 2009. Despite her original intentions to pursue research in alternative energy, she joined Joseph DeSimone’s lab at the University of North Carolina at Chapel Hill and has performed her PhD research in pulmonary drug delivery. At the time of this dissertation, the author intends to continue academic research and has accepted the University of Michigan President’s Postdoctoral Fellowship to continue in the field of drug delivery with precision engineered biomaterials. iii ACKNOWLEDGEMENTS Where to start! This PhD process has involved the help and support of so many people who have shaped me into the person I am today. I am beyond grateful to have had such fantastic support throughout these past five years and consider myself quite blessed. First and foremost, I would like to thank my advisor Joe DeSimone, who picked me out of a crowd of wide-eyed first year graduate students and welcomed me into his group. The opportunities that he has catalyzed for me have been immeasurable, exposing me to projects, people, and experiences I never would have believed were possible. Thank you very much for your continued belief in my potential, even when I wasn’t sure of it myself, and for your invaluable support and encouragement to differentiate myself and pursue the unknown. I am truly in your debt and look forward to your continued support in my future endeavors! Next, I would like to thank my NCSU Chemical Engineering family, who, despite my departure to Chapel Hill, has remained steadfast in their support. I regret the many missed conversations and collaborations that I can only envision would have transpired if I had remained local. First, I am incredibly thankful to my committee members: Dr. Orlin Velev, Dr. Saad Khan, and Dr. Michael Dickey. Their continued patience, flexibility, friendship, and scientific advice has helped me maintain my roots in Chemical Engineering and their willingness to engage with my unconventional research direction is greatly appreciated (especially as they embark on reading this dissertation!). I am also hugely thankful to Dr. Dickey for providing me the opportunity to guest lecture in his introductory Chemical Engineering class and the encouragement to better my teaching skills. I would also like to specifically thank a number of CHE faculty, including Dr. Fedkiw, Dr. Genzer, Dr. Haugh, Dr. Ollis, Dr. Reeves and Dr. Hall, who have each in some way positively contributed to my time at NCSU. Finally, I would never have navigated the logistics of graduate school without the incredible support of Ms. Sandra Bailey – thank you! In missing out on more experiences at NCSU, I was lucky to gain incredible connections throughout many departments at UNC. First, I need to thank Dr. Jenny Ting of the Immunology department, for providing me intellectual support and resources of her lab. iv Some weeks, I spent more time in her lab than my own, and I appreciate her patience as I monopolized her students’ time. I am hugely thankful for the opportunity to work with Reid Roberts, who first introduced me to immunoengineering and is one of the most insightful and inspiring scientists I’ve ever met. I appreciate the coaching of Coy Allen, who taught me all of the lung animal techniques. A thank you also goes to other members of the Ting lab, including Alex, Justin, Yoshi, Aga, Cate, Tim, Les, Leo, Emily and Elizabeth for making me feel at home. I also was known to frequent the lab of David Leith in the Environmental Engineering lab, for which I am extremely grateful. He provided me with the first direction in aerosol characterization and allowed me unrestricted access to his resources. I am incredibly thankful for his expertise. I also received overwhelming assistance from Maryanne Boundy and Joe Pedit and their practical experience and technical support was essential to my success. Next, I would like to acknowledge the professional guidance and mentorship of Ben Maynor and Pete Mack. Through our initial collaborations between the DeSimone lab and the Liquidia Inhalation team, I was fortunate to receive extremely helpful technical input from both Ben and Pete, who exposed me to the industrial size of the pharmaceutical industry. I have very fond memories of conversations at conferences, lunch meetings, or sample exchanges and their mentorship is greatly appreciated. I was also fortunate to receive personal and professional guidance from two special lab managers. I would like to thank Mary for teaching me how to thrive in the DeSimone lab, leading by example, and for encouraging me when I needed it most. I would also like to thank Chris for his willingness to lend an ear, his conviction in my abilities, his much needed life advice, and most importantly, his friendship. Professionally, I would like to thank a number of colleagues at UNC who have enabled my research. Thanks to Amar Kumbhar and Carrie Donley from CHANL for providing technical SEM support. Thanks to Charlene Santos, Alain Valdivia and Mark Ross of the UNC Lineberger Animal core for assistance with injections, housing and care, as well as the entire DLAM staff. Thanks also to Donald, Reggie and Erica, who always managed to brighten my day. v At this point, I would also like to acknowledge my funding support from the NIH Pioneer Award (1DP1OD006432)
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