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Development of a Qtsome Lipid Nanoparticle Delivery Platform for Oligonucleotide

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Development of a Qtsome Lipid Nanoparticle Delivery Platform for Oligonucleotide Development of a QTsome Lipid Nanoparticle Delivery Platform for Oligonucleotide Therapeutics DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Jilong Li Graduate Program in Pharmaceutical Sciences The Ohio State University 2018 Dissertation Committee: Robert J. Lee Ph.D. Advisor Sashwati Roy Ph.D. Co-Advisor Mitch A. Phelps Ph.D. Yizhou Dong Ph.D. Copyright by Jilong Li 2018 Abstract The objective of this dissertation thesis is to develop a novel lipid nanoparticle oligonucleotide delivery platform with pH responsive lipid combination and enhancement ligands to achieve therapeutic goals in cancer and wound management. Favored by numerus scientists and pharmaceutical industries, gene therapy has received a lot of compliments and has been extensively studied over many decades. A series of pre-clinical and clinical trials have revealed superior efficacy over conventional chemo-drugs on many genetic disorder diseases including cancer, inflammation, neural degenerative disease, hereditary disease. However, successful commercialization of gene therapy has been compromised due to several unfavorable properties. Naked oligonucleotides are considerably unstable due to chemical and enzymatic cleavage during manufacture and administration. Additionally, incapability of penetrating cell membranes due to high polarity and charge density has forbidden its bench-side application via conventional formulations. Moreover, highly-potent and long-last efficacy of gene therapeutics has compelled the demands for target-specific delivery to avoid off- target side effects or cytotoxicity. Hence, carefully engineered and delicate development of novel delivery system specifically designed for gene therapy has been called upon by research scientists and medical practionors. ii In Chapter 2, we have proposed a well-designed pH responsive lipid nanoparticle delivery platform (QTsome) with enhanced in vitro &in vivo gene trafficking efficacy to treat non-small cell lung cancer (NSCLC). The novelty of such pH responsive platform is substantially improved endosomal escape facilitated by the combination of quaternary and tertiary amine based cationic lipids. Three lead advantages can be acquired based on quaternary/tertiary cationic combination: firstly, near neutral or weak positive surface charges can be micro-adjusted to achieve optimal interactions between delivery system and targeting cells, while avoiding drawbacks including cytotoxicity and RES clearance associated with traditional cationic lipid nanoparticles; secondly, higher oligo encapsulation efficiency can be achieved by mixing the oligo cargos with lipid compositions at pH~4.0 to introduce stronger electrostatic interactions; thirdly, enhanced release of gene cargos into cytoplasm is introduced by presence of highly positive charges in late endosome stage. In our study, encapsulated anti-miR-21 has shown excellent stability and loading capacity within the QTsome, along with more than 50% of miR-21 suppression. Additionally, combinational therapy facilitated by incorporation of PTX (Paclitaxel) into QTsome/ anti-miR-21 has demonstrated greater capacity in cell proliferation inhibition and metastasis reduction. In Chapter 3, QTsome platform has been further adjusted to accommodate chronic wounds. To further improve in vivo transfection efficiency, ionophore reagent Gramicidin A was incorporated into the formulation. Gramicidin A has been proposed to enhanced cell penetration capacity as well as endosomal escape via promoting hexagonal II (HII) phases. QTsome surface properties have been carefully studied to in adaption to iii the presence of phagocytes and macrophages on the wound bed. Anti-miR-210 has been successfully inserted into keratinocytes to reverse ischemia memory of proliferation cease. Results have suggested restoration of basal keratinocyte cell hyper-proliferation and migration in mice ischemic wound models. In Chapter 4, a keratinocytes-specific targeting ligand has been conjugated onto the surface of QTsome to enhance cell-specific recognition. Studies have pointed out complications and side effects involved in non-specific targeting. Deep-burn wound bed environment has recruited a variety of cell types including bacteria, macrophage, phagocyte, fibroblast, keratinocyte. Random delivery of high potent oligo cargos has great potentials in causing unknown therapeutic outcomes and severe toxicities. Therefore, target delivery of miR cargos into specific cells without detection from surrounding tissues have become the major barrier to break. In this study, we have proposed a sophisticated designed targeting delivery system loaded with anti-miR-107 that is capable of keratinocytes recognition and accelerating wound closure and restoration of barrier function. In addition, lyophilization has been incorporated to accommodate a non-injection route of application with additional long-term storage capacity. iv Dedication This document is dedicated to my beloved family. v Acknowledgments Firstly, I would like to give my most sincere appreciation to my primary advisor, Dr. Robert J. Lee, for all the support, tutoring, and encouragement throughout all these years. I have been greatly inspired by his depth of knowledge, his way of carrying out an independent research and his creative thought of problem shooting. I would not be able to properly and successfully complete my doctoral degree without his inspiration and support. Additionally, I would also like to thank my co-advisor Dr. Sashwati Roy for providing such precious opportunity to work as a team member in Sen lab and for her patient mentorship and expertise on wound healing project. I am very grateful to faculty members from College of Pharmacy including Dr. Yizhou Dong and Dr. Mitch A. Phelps, who kindly accept my request to serve committee members for candidacy examination and final defense examination. I deeply appreciate their generosity for their valuable time and helpful advice on my candidacy proposal and dissertation thesis. I would also like to thank Dr. Chandan K Sen for his support on my graduate study and wound healing projects. Secondly, I would like to thank my lab mates and colleagues: Dr. Bryant C. Yung, Dr. Hong Li, Dr. Mengzi Zhang, Dr. Subhadip Ghatak, Dr. Surya C. Gnyawali, Dr. Mohamed S El Masry, Dr. Das Amitava for their valuable insights and inspiring discussions on my projects. I truly appreciate Dr. Xin Xin, Dr. Dongzhu Wu, Mr. Xinwei vi Cheng, Mr. Yang Liu, for their friendly help throughout my study at OSU. Plus, I would like to thank all the friends and loved ones for being a part of my memorable journey at the Ohio State University. Lastly, and most importantly, I would like to give my sincere thanks to my parents for their unconditional support on my good times and bad times through all these years. They have been continuously encouraging me and give me all their understandings for me to carry on. I wouldn’t stand a single chance to have accomplished this much on my journey without their love. vii Vita 1988…………………………................Born--Chengdu, P.R. China 2006-2010………………………….......B.S. Pharmacy, Southern Medical University, Guangzhou, China 2010-2012………………………….......M.S. of Pharmaceutical Science, University of Pittsburgh 2012-present…………………………...Graduate Research Associate, Department of Pharmaceutics and Pharmaceutical Chemistry, The Ohio State University Publications Ghatak S, Li J, Chan YC, Gnyawali SC, Steen E, Yung BC, Khanna S, Roy S, Lee RJ, Sen CK. AntihypoxamiR functionalized gramicidin lipid nanoparticles rescue against ischemic memory improving cutaneous wound healing. Nanomedicine. 2016 Mar 29. Yung BC*, Li J*, Zhang M, Cheng X, Li H, Yung EM, Kang C, Cosby LE, Liu Y, Teng L, Lee RJ. Lipid Nanoparticles Composed of Quaternary Amine-Tertiary Amine Cationic Lipid Combination (QTsome) for Therapeutic Delivery of Anti-miR-21. Mol Pharm. 2016 Jan 19. (* These authors contribute equally to this paper) viii Jaime-Ramirez AC, McMichael EL, Kondadasula S, Skinner CC, Mundy-Bosse BL, Luedke E, Jones NB6, Mani A, Roda J, Karpa V, Li H, Li J, Elavazhagan S, La Perle KM, Schmitt AC, Lu Y, Zhang X, Pan X, Mao H, Davis M, Jarjoura D, Butchar JP, Poi M, Phelps M, Tridandapani S, Byrd JC, Caligiuri MA, Lee RJ, Carson WE. The NK Cell- mediated Anti-tumor Effects of a Folate-conjugated Immunoglobulin are enhanced by Cytokines. Cancer Immunol Res. 2016 Feb 10. Li J, Ghazwani M, Zhang Y, Lu J, Li J, Fan J, Gandhi CR, Li S. miR-122 regulates collagen production via targeting hepatic stellate cells and suppressing P4HA1 expression. J Hepatol. 2013 Mar; 58(3):522-8. Zhang X, Sun X, Li J, Zhang X, Gong T, Zhang Z. Lipid emulsions loaded with doxorubicin-oleic acid ionic complex: characterization, in vitro and in vivo studies. Pharmazie. 2011 Jul; 66(7):496-505. Field of Study Major field: Pharmaceutical sciences ix Table of Contents Abstract ............................................................................................................................... ii Dedication ........................................................................................................................... v Acknowledgments.............................................................................................................. vi Vita ................................................................................................................................... viii Table of Contents ...............................................................................................................
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