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Copyright © 2019 by Yue Wu Studies in Using Gold Nanoparticles in Treating Cancer and Inhibiting Metastasis A Dissertation Presented to The Academic Faculty by Yue Wu In Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the School of Chemistry and Biochemistry Georgia Institute of Technology May 2019 COPYRIGHT © 2019 BY YUE WU Studies in Using Gold Nanoparticles in Treating Cancer and Inhibiting Metastasis Approved by: Dr. Mostafa A. El-Sayed, Advisor Dr. Robert Dickson School of Chemistry and Biochemistry School of Chemistry and Biochemistry Georgia Institute of Technology Georgia Institute of Technology Dr. Ingeborg Schmidt-Krey Dr. Zhong Lin Wang School of Chemistry and Biochemistry School of Material Science and Georgia Institute of Technology Engineering Georgia Institute of Technology Dr. Ronghu Wu School of Chemistry and Biochemistry Georgia Institute of Technology Date Approved: March 26, 2019 To My Family ACKNOWLEDGEMENTS First, I would like to thank my advisor, Prof. Mostafa A. El-Sayed, for his guidance, encouragement, support, sharing with me his life-long enthusiasm and dedication towards scientific research, and the opportunity he provided me to move into the nanotechnology and nanomedicine field. His optimistic, positive, modest, and humorous personality is always inspiring me. I would also like to acknowledge the professors during my PhD time, including Prof. Ning Fang, for his guidance of optical imaging and great support for my research, Prof. Todd Sulchek for his help with cell mechanical measurement, Profs. Ronghu Wu, Fangjun Wang, and Facundo Fernandez for their help with mass spectrometry based proteomics and metabolomics, Profs. Ivan El-Sayed and Dong Shin for their guidance on animal work or clinical applications, and Prof. Michelle Dawson for her guidance on cytoskeleton and cell migration. I would like to express gratitude to my thesis committee members — Profs. Ingeborg Schmidt- Krey, Ronghu Wu, Robert Dickson, and Zhong Lin Wang — your encouragement, support, and valuable discussions are very much appreciated. Second, I am very grateful to have the chance to work with some really talented postdocs and students during the past several years. I would like to especially acknowledge Dr. Moustafa Ali, for his great knowledge and skills that he shared with me and his continuous guidance and support. I am very grateful to have worked with him throughout my entire Ph.D. program. I also would like to thank Dr. Kuangcai Chen for his help with differential interference contrast microscopy, Dr. Bin Dong for his help with Stochastic Optical Reconstruction Microscopy (STORM), Drs. Tiegang Han and Yan Tang for their help in bioinformatics analysis, Drs. Haopeng Xiao, Jin Chen, and Xiaoling Zang for their help with mass spectrometry iv measurements, Dr. Deepraj Ghosh for his help with cell migration assays, Mr. Brian Do for atomic force measurement, Ms. Sommer Durham for flow cytometry trainings, and Dr. Eric Snider for his help in Western-blot analysis. In addition, I would like to thank all the undergraduate research assistants that were working with me in time order— Kamillah Kassam, Savita Chapman, Sarah Ghalayini, Tessneem Belhadj Yahya, Mostafa Ayman Riad Nasser, Cassidy Tobin, Cecily Ritch, Arusha Siddiqa, Tsion Assaye, Sreenath Raparti, Ahmed Amer, Samuel Nelson, Shreyas Krishnapura, Hashem Mohilldean, Kamaria Dansby, Ziyan Wu, Paige Warner, and Arfa UI-Haque, etc — it has been a pleasure working with you and I wish you all the best moving forward. My labmates, Dr. Sajanlal R. Panikkanvalappil, Mr. Mohammadreza Nazemi, Dr. Xiongwu Kang, Dr. Nasrin Hooshmand, Dr. Cheng Xu, Dr. Hongje Jang, etc — thanks for your support and help. I’d also like to thank Ms. Michele Yager, Dr. Kenyatta Johnson, Ms. Tracy Johns, and Mr. Mike Riley for their help for administration, fund applications, and guidance in my PhD program. Lastly, I would also like to give my special acknowledgements to my family. Mom and Dad, thank you for raising me and Hao, teaching us to work hard and help people, inspiring me to realize my potential and encouraging me to achieve my dreams. My husband, Xiao, thank you for your great understanding, love, patience, and support for my life and work. I feel very lucky to have met you in Georgia Tech. I also thank all my friends. Without your great help and support over the years, none of this would ever have happened. v TABLE OF CONTENTS ACKNOWLEDGEMENTS iv LIST OF TABLES viii LIST OF FIGURES iv LIST OF SYMBOLS AND ABBREVIATIONS xvii SUMMARY iv CHAPTER 1. Introduction 1 1.1 Introduction of Gold Nanoparticles 1 1.1.1 Synthesis of Gold Nanoparticles 2 1.1.2 Physical and Optical Properties of AuNPs 4 1.2 Gold Nanoparticles for Cancer Treatment 6 1.2.1 Plasmonic Photothermal Therapy 6 1.2.2 AuNPs in Inhibiting Cancer Metastasis 12 1.2.3 Biodistribution, pharmacokinetics and toxicity of gold nanoparticles 21 1.3 Motivation of the Work 31 CHAPTER 2. Gold Nanoparticles for Biological Diagnosis and Imaging 34 2.1 Current Advance of Using Gold Nanoparticles in Biological Optical Imaging and Sensing [135] 35 2.1.1 Introduction 35 2.1.2 Direct Visualization of Gold nanoparticles in Biological Systems 37 2.1.3 Molecular Fingerprinting by Surface-enhanced Raman Scattering (SERS) 52 2.1.4 Conclusions and future outlook 60 2.2 Simultaneous Time Dependent Surface-Enhanced Raman Spectroscopy Reveals Cancer Death Mechanisms Associated With Gold Nanorod Photothermal Therapy[192] 63 2.2.1 Introduction 64 2.2.2 Methods 66 2.2.3 Results 75 2.2.4 Discussion. 97 2.3 Improving the Flow Cytometry-based Detection of Gold Nanoparticle Cellular Uptake 102 2.3.1 Introduction. 102 2.3.2 Methods. 105 2.3.3 Results 109 2.3.4 Discussion 116 2.3.5 Conclusion. 117 CHAPTER 3. Gold Nanoparticles Changes the Mechanical Properties of Cancer Cells in Inhibiting the Cancer Cell Migration and Invasion 119 vi 3.1 Nuclear Membrane-targeted Gold Nanoparticles Inhibit Cancer Cell Migration and Invation [85] 119 3.2 Introduction 121 3.3 Methods 123 3.4 Results and Discussion 131 3.4.1 Gold Nanoparticle Synthesis, Conjugation, Cellular Uptake and Cytotoxicity Measurements 131 3.4.2 Nuclear Targeting Gold Nanoparticles Inhibit Cancer Cell Migration and Invasion 137 3.4.3 Nuclear Targeting Gold Nanoparticles Enhance Nuclear Stiffness 139 3.4.4 AuNPs Accumulate at Nuclear Membrane Resolved by Three Dimensional Microscopy 142 3.4.5 Nuclear Targeting Gold Nanoparticles Cause Lamin A/C Protein Increase. 145 3.5 Conclusions 148 CHAPTER 4. Molecular Understanding of Gold Nanoparticles and Plasmonic Photothermal Effect in Inhibiting Cancer Cell Migration 150 4.1 Targeting Cancer Cell Integrins Using Gold Nanorods in Photothermal Therapy Inhibits Migration Through Affecting Cytoskeletal Proteins[10] 150 4.1.1 Introduction. 151 4.1.2 Methods. 155 4.1.3 Results. 161 4.1.4 Discussion. 176 4.2 Gold Nanorod-photothermal Theralpy Alters Cell Junctions and Actin Network in Inhibiting Cancer Cell Collective Migration[94] 179 4.2.1 Introduction. 180 4.2.2 Results and Discussion. 182 4.2.3 Methods. 207 4.2.4 Conclusion. 219 CHAPTER 5. Gold Nanoparticles and Plasmonic Photothermal Effect on Animals in Inhibiting Metastasis 220 5.1 Gold Nanorod-assisted Photothermal Therapy Decreases Bleeding During Breast Cancer Surgery on Dogs and Cats 220 5.1.1 Introduction. 221 5.1.2 Methods. 223 5.1.3 Results and Discussion. 226 5.1.4 Conclusion. 234 5.2 A Mechanistic Analysis of Gold Nanorod-assisted Photothermal Therapy on a Cat with Contentious Mammary Gland Tumor. 235 5.2.1 Methods. 236 5.2.2 Results and discussions. 239 5.2.3 Conclusion. 243 REFERENCES 244 VITA 271 vii LIST OF TABLES Table 2.1. Zeta potential results for AuNRs with different surface modifications ........... 77 Table 2.2. Tentative assignment of Raman bands in the SERS spectra collected from HSC cells 266,271. ................................................................................................................................. 85 Table 3.1. Zeta potential of AuNPs with different surface ligands ................................ 133 Table 4.1. Selected significantly dysregulated phosphorylation sites of the cytoskeletal and junction proteins, specifying the phosphorylation sites and biological functions. ......... 196 Table 5.1. Animal groups, tumor clinical features, and therapeutic approaches ............ 232 Table 5.2. Survival, bleeding loss and met astasis for both GI and GII ......................... 234 viii LIST OF FIGURES FIGURE 1.1. Gold nanoparticle and light interacting: surface plasmon resonance (SPR). Adapt from Website: https://scholar.harvard.edu/ndurr/pages/multiphoton-luminescence-imaging. ............................................................................................................................................. 5 FIGURE 1.2 Tunability of the SPR of AuNRs. (a-f) TEM images of AuNRs with different aspect ratios (length of a rod divide by its width). Reprinted with permission from [4]. Copyright 2006 American Chemical Society. (g) Tuning longitudinal SPR by synthetically controlling aspect ratio. Reprinted with permission from [20]. Copyright 2006 American Chemical Society . 5 FIGURE 1.3. (a-b) AuroLase® treatment of canine transmissible venereal tumor in brain of a dog. MR-DCE axial images of dog brain showing contrast enhancement of bilobed tumor (a) before and (b) ablation of tumor after treatment. Reprinted with permission from ref [32]. Copyright 2009 American Association for Cancer Research. (c) Our study showed the tumor regression curves from 13 mammary
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