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Assembly of Phi29 Prna Nanoparticles for Gene Or Drug

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Assembly of Phi29 Prna Nanoparticles for Gene Or Drug Assembly of Phi29 pRNA Nanoparticles for Gene or Drug Delivery and for Application in Nanotechnology and Nanomedicine A dissertation submitted to The Division of Research and Advanced Studies, University of Cincinnati In partial fulfillment of the requirements for the degree of Doctor of Philosophy In the Biomedical Engineering Program School of Energy, Environmental, Biological and Medical Engineering College of Engineering and Applied Science 2012 by Yi Shu M.S. Chinese Center for Disease Control and Prevention (CCDC), China, 2007 B.S. Lanzhou University, China, 2004 Committee Chair: Jing-Hui Lee, Ph.D Co-chair: Peixuan Guo, Ph.D ABSTRACT RNA nanotechnology is to extract defined RNA structure motifs and tertiary interactions, apply them as the building blocks to self-assemble nano-scaled scaffolds with rational designs, and incorporate functional molecules such as siRNA, ribozyme, aptamer and therapeutical compounds to form functionalized RNA nanoparticles. Bacteriophage phi29 packaging RNA (pRNA) has two defined domains: the 5’/3’-end helical domain and the interlocking loop region which is located at the central part of the pRNA sequence. pRNA dimer is formed by hand-in-hand interaction via 4-bp interlocking base pairing. The dimeric pRNA nanoparticle has been shown to be an efficient vector for the specific delivery of small interfering RNA (siRNA) into specific cancer or viral infected cells. However, there are several problems hindering the therapeutic applications of pRNA nanoparticles. In this thesis, I will try to address: 1) The problem of large-scale synthesis of longer RNA molecules. Industrial scale production of RNA by chemical synthesis is limited to ~ 80nt. In order to chemically synthesize pRNA and its functionalized chimeric constructs (generally > 120 nt) in large scales, pRNA nanoparticles were constructed using two synthetic RNA fragments within the size limit for chemical synthesis. The resulting bipartite pRNAs were competent to form dimers, package DNA via the nanomotor, and assemble phi29 phage in vitro. The pRNA subunit assembled from bipartite fragments harboring siRNA or receptor-binding ligands were equally competent in binding cancer cells specifically, entering the cell, and silencing specific genes of interest as the intact constructs. 2) The problem of RNA degradation. 2’-fluorine (2’-F) modification was introduced into the RNA sugar ring and the modified RNAs were resistant to RNase degradation and suitable for in vivo delivery. 3) The dissociation problem of pRNA nanoparticles. The lack of covalent linkage or crosslinking in nanoparticles causes dissociation ii of pRNA nanoparticles while present in diluted condition in vivo. Chemical crosslinking methods such as psoralen crosslink were adapted to stabilize the tertiary structure of the pRNA nanoparticles. To further improve pRNA nano-deliver systems, we constructed novel pRNA delivery platform based either on enhanced loop-loop interactions or branched RNA three-way junction (3WJ) or derived X-shaped motifs. The wild-type pRNA loop-loop interaction was extended from 4bp to 7bp. The correct folding of the loop-extended pRNAs was predicted by Mfold and further confirmed by efficient dimer formation in native PAGE. Stronger loop-loop interaction was observed as indicated by observation of higher ordered structure formation in native gel. Via this stronger loop-loop interaction and end-palindrome sequence, varieties of pRNA nanoparticles, including hexamer with six functionalities were constructed. Meanwhile, functionalities were also conjugated into pRNA 3WJ or 3WJ derived X-shaped scaffold and self- assembled into thermodynamically stable and multifunctional nanoparticles. This novel nano- delivery system was proved to be capable of delivering siRNA into cancer cells specifically. Due to its multi-valence, multiple copies of siRNAs for same target or siRNAs for different targets were conjugated into one particle to enhance gene silencing effects, which paves a new way to apply RNA nanotechnology and nanomedicine for cancer therapy and viral disease treatment. iii iv ACKNOWLEDGMENTS I would like to express my deepest gratitude to my thesis advisor, Dr. Peixuan Guo, for his guidance and support which make this thesis possible. I am very grateful that I was offered this great opportunity to work on these challenging projects for my PhD studies at University of Cincinnati and University of Kentucky. My sincerest gratitude also goes to my co-advisor and committee chair, Dr. Jing-Huei Lee, committee members, Dr. Malak Kotb and Dr. Andrew Herr, for their helpful advice and support; my Ph.D qualifying exam committee, Dr. Carlo Montemagno, Dr. Jarek Meller, Dr. Marepalli Rao for providing invaluable suggestions on my written proposal and oral defense. The members of the Dr. Guo’s laboratory have been a source of informative instruction, collaboration as well as friendships. I would like to give my sincere thanks especially to Dr. Dan Shu, Dr. Hui Zhang, and Dr. Feng Xiao for their immense help to my personal and professional life during my PhD study and I am also grateful to many of past and present lab colleagues: Dr. Farzin Haque, Dr. Randall Rief, Dr. Zhanxi Hao, Dr. Oana Coban, Dr. Faqing Yuan, Dr. Wenjuan Wang, Dr. Tae Jin Lee, Dr. Matthieu Cinier, Dr. Peng Jing, Dr. Anne Vonderheide, Dr. Gianmarco De Donatis, Shuhui Wan, Jing Liu, Wei Li, Jia Geng, Huaming Fang, Chad Schwartz, Daniel Binzel, Le Zhang, Fengmei Pi, Zhengyi Zhao, Hui Li, Shaoying Wang, and Nayeem Hossain for their kind help and support. I am also thankful to all the work-study students in Guo’s laboratory. I would like to thank my collaborators: Dr. Jiehua Zhou and Dr. John Rossi from City of Hope for the collaboration on the HIV project; Dr. Zhenqi Zhu and Dr. Malak Kotb from College of Medicine at University of Cincinnati for the collaboration on Leukemia project; Dr. Pheruza Tarapore and Dr. Shuk-Mei Ho from College of Medicine at University of Cincinnati for the v collaboration on Ovarian Cancer project; Dr. Piotr Rychahou and Dr. B. Mark Evers from Markey Cancer Center at University of Kentucky for the collaboration on Colon Cancer project; Jing Hu and Dr. Jiukuan Hao from College of Pharmacy at University of Cincinnati for the collaboration on Liver Cancer project; Dr. Dingxiao Zhang and Dr. Xiaoting Zhang from College of Medicine at University of Cincinnati for the collaboration on Breast Cancer project. Their kind help and hard work make projects moving forward and greatly enrich my learning experience. Many thanks to Dr. Matthieu Cinier and Shuhui Wan for their help with the synthesis of folate-DNA strand; Dr. Nourtan Abdeltawab and Dr. Zhenqi Zhu from Dr. Malak Kotb’s laboratory at the University of Cincinnati for the help with qRT–PCR assays; Sejal Fox from Dr. Nira Ben-Jonathan’s laboratory at the University of Cincinnati for help handling flow cytometer and data analysis; and Birgit Ehmer from University of Cincinnati for the assistance on Confocal Microscopy. I would like to thank all the staff members and our faculties, especially the graduate coordinators Julie Muenchen and Barbara Carters, in College of Engineering and Applied Sciences at University of Cincinnati for their kind help. Finally, I would like to express my deepest love and appreciation to my family, my mother Xiaoli Fan and my farther Zhaoyuan Shu. Their encouragement and support are my motivations all the time. My Ph.D projects were supported by National Institutes of Healthy grants R01-GM59944, EB003730, EY018230 “NIH Nanomedicine Development Center: Phi29 DNA packaging Motor for Nanomedicine”, and National Cancer Institute funding U01-CA151648 to Dr. Peixuan Guo. vi TABLE OF CONTENTS Abstract ........................................................................................................................................ii Acknowledgements ......................................................................................................................v Table of Contents .....................................................................................................................vii List of Tables ................................................................................................................................x List of Figures ...............................................................................................................................xi Chapter 1 Introduction and Literature Review .........................................................................1 Lipid based nanoparticles ........................................................................................................ 2 Polymer based nanoparticles .....................................................................................................5 Carbohydrate based nanoparticles…………….........................................................................7 Virus based nanoparticles (VPNs).............................................................................................8 Protein and peptide based nanoparticles ...................................................................................9 Inorganic nanoparticles .......................................................................................................... 10 DNA nanotechnology ............................................................................................................ 11 RNA nanotechnology ............................................................................................................
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