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The Role of Tumor Desmoplasia in Nanoparticle Delivery of Drugs and Genes

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The Role of Tumor Desmoplasia in Nanoparticle Delivery of Drugs and Genes THE ROLE OF TUMOR DESMOPLASIA IN NANOPARTICLE DELIVERY OF DRUGS AND GENES Lei Miao A dissertation submitted to the faculty at the University of North Carolina at Chapel Hill in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Division of Molecular Pharmaceutics in the Eshelman School of Pharmacy Chapel Hill 2016 Approved by: Leaf Huang Philip C. Smith Elena V. Batrakova Xiao Xiao William Y. Kim © 2016 Lei Miao ALL RIGHTS RESERVED ii ABSTRACT Lei Miao: The Role of Tumor Desmoplasia in Nanoparticle Delivery of Drugs and Genes (Under the direction of Leaf Huang) In desmoplastic tumors, stroma cells capture nanoparticles (NPs), preventing them from reaching tumor cells, resulting in compromised anti-tumor efficacy. This dissertation focuses on understanding the basis role of tumor associated fibroblasts (TAFs), one of the major stroma cells constituting desmoplasia, in NP delivery and tumor resistance, as well as proposing strategies to overcome the TAF-elicited barriers and improve efficacy. While the capture of therapeutic NPs in TAFs interferes tumor-stroma crosstalk and inhibits tumor progression, we found that the chronic exposure of NPs paradoxically induced the secretion of survival factors (e.g., Wnt16) from the damaged TAFs, facilitating tumor proliferation and metastasis. Therefore, we proposed the delivery of siRNA against Wnt16 to TAFs via the off-target capture, to downregulate this survival factor. The priming of damaged fibroblasts could synergize with a nanoformulation of cisplatin, and benefit the treatment of a desmoplastic bladder cancer xenograft (UMUC3/3T3). Since the off-target delivery of NPs have been verified, we further utilized the same rationale to generate a group of tumor-suppressive TAFs through transfecting TAFs with a plasmid encoding highly secretable TNF-related apoptosis-inducing ligand (sTRAIL). The production of sTRAIL from TAFs bypassed the stroma barrier and resulted in efficient killing of tumor cells. Furthermore, we also proposed a stroma depletion method via combination therapy of cisplatin NPs and gemcitabine NPs. This combination was not only detrimental to tumor cells, but induced superior apoptosis in TAFs of the UMUC3/3T3 model. To ensure the sufficient synergy, we further designed a nano-formulation with ratiometric co-loading and co-delivery of these two regimens. The design of converting these two drugs with totally different physicochemical properties iii into nano-cores with similar hydrophobic surface and particle size, allows for their simultaneously and ratiometric loading in a single PLGA NPs. This combinatory NPs showed potent anti-cancer efficacy compared to each regimens in separate NPs. In summary, the stroma modulating strategies proposed in the current dissertation provide new paradigms for the treatment of desmoplastic tumors. Combined with cancer immunology, a more prolonged and efficient outcome can be anticipated. The ratiometric combination nano-platform also provides a promising approach for encapsulating agents with different physicochemical properties. iv To my parents Xingwang Miao and Guihua Huang v ACKNOWLEDGEMENTS First of all, I would like to express my utmost gratitude and appreciation to my supervisor, Dr. Leaf Huang who offered me this great educational opportunity in his lab as a graduate student. In the past few years, he provided me constant support, priceless guidance and extraordinary wisdom throughout my PhD journey. He is a remarkable and exceptional mentor I am so blessed to have. I will be forever thankful to his mentorship, inspiration and sense of humor. I would also like to thank my committee members, Dr. Elena Batrakova, Dr. Xiao Xiao, Dr. William Kim and Dr. Philip Smith for their precious guidance throughout the years. They advised me through the obstacles in completion of my research work and reviewed all my progress and dissertation. In addition, I would like to extend my special appreciation to Dr. Gregory Forest, Dr. Samuel Lai, Dr. Shawn Hingtgen, Dr. Shutao Guo, Dr. Yuhua Wang and Dr. Jing Zhang for their collaboration and as my external advisors. Moreover, I want to express my gratitude to UNC Eshelman School of Pharmacy for allowing me pursuing higher education. I also like to acknowledge my colleagues and friends, C. Michael Lin, Lu Zhang, Yao Lu, Yi Zhao, Qi Liu, Ning Cheng, Xiaomeng Wan, Qiaoxi Li, Andrew Satterlee, Matt Haynes, Tyler Goodwin, Yang Xiong, Lina Liu, and all past and present members of the Huang Laboratory for their sincere friendship and kindly help throughout my graduate study. Particularly, I will never forget the happiness, frustration, jokes, and parties we had in addition to the inspiring scientific conversations. I would like to acknowledge BRIC imaging core facility, Flow Cytometry core facility, Animal Pathology core facility, ICP-MS core facility, CHANL for their assistance especially Dr. Hong Yuan, Dr. Wallace Ambrose, Nazar Filonov, and Charlene Santos. vi I would particularly thank my parents, my brothers and sisters for their unconditional support and love all along the journey. I cannot go this far without their understanding, patience, standing by my side, faith and love. vii TABLE OF CONTENTS LIST OF TABLES ................................................................................................................................ xi LIST OF FIGURES .............................................................................................................................. xii LIST OF ABBREVATIONS AND SYMBOLS ................................................................................. xvi CHAPTER 1: STROMAL BARRIERS AND STRATEGIES FOR THE DELIVERY OF NANOMEDICINE TO DESMOPLASTIC TUMORS ............................................... 1 1.1 Summary ................................................................................................................................ 1 1.2 Introduction ............................................................................................................................ 2 1.3 Mathematical Modeling and In Vitro Models of NP Intratumoral Distribution .................... 3 1.4 Enhanced Permeability and Retention Effect and Anti-cancer NPs in the Clinical Trials .... 5 1.5 Tumor Microenvironment Barriers for Intratumoral NPs Diffusion and Distribution .......... 6 1.6 Physicochemical Properties of NPs influences NPs transport in Stroma-rich Tumors ....... 14 1.7 Strategies to Improve NPs extravasation and Penetration ................................................... 17 1.8 Conclusions and Future Perspectives .................................................................................. 26 CHAPTER 2: THE BINDING SITE BARRIER ELICITED BY THE TUMOR ASSOCIATED FIBROBLASTS INTERFERES DISPOSITION OF NANOPARTICLES IN THE STROMA-VESSEL TYPE DESMOPLASTIC .................................... 33 2.1 Summary .............................................................................................................................. 33 2.2 Introduction .......................................................................................................................... 34 2.3 Methods and Materials......................................................................................................... 35 2.4 Results.................................................................................................................................. 47 2.5 Discussion ............................................................................................................................ 56 viii CHAPTER 3: PRIMING OF THE DAMAGED TUMOR ASSOCIATED FIBROBLASTS ENHANCES THERAPEUTIC EFFICACY OF CISPLATIN NANOPARTICLES FOR DESMOPLASTIC BLADDER CANCER TREATMENT ....................... 77 3.1 Summary .............................................................................................................................. 77 3.2 Introduction .......................................................................................................................... 78 3.3 Materials and Methods......................................................................................................... 80 3.4 Results.................................................................................................................................. 91 3.5 Discussion and Conclusion ................................................................................................ 102 CHAPTER 4: IN SITU GENERATION OF TUMOR-SUPPRESSIVE FIBROBLASTS BY HARNESSING OFF-TARGET DISPOSITIONS OF NANOPARTICLES IN TUMOR ASSOCIATED FIBROBLASTS ................................................. 124 4.1 Summary ............................................................................................................................ 124 4.2 Introduction ........................................................................................................................ 125 4.3 Materials and Methods....................................................................................................... 127 4.4 Results................................................................................................................................ 135 4.5 Discussion and Conclusion ................................................................................................ 144 CHAPTER 5: SYNERGISTIC DEPLETION OF TUMOR ASSOCIATED FIBROBLASTS VIA COMBINED GEMCITABINE AND CISPLATIN NANOPARTICLES IMPROVES DESMOPLASTIC BLADDER CANCER TREATMENT ........
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