PET/MR IMAGING OF ATHEROSCLEROTIC PLAQUE AND TUMOR USING DUAL MODALITY SPIOS A Dissertation Presented to The Academic Faculty by Nazanin Masoodzadehgan In Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the School of Engineering Georgia Institute of Technology December 2014 Copyright © Nazanin Masoodzadehgan 2014 PET/MR IMAGING OF ATHEROSCLEROTIC PLAQUE AND TUMOR USING DUAL MODALITY SPIOS Approved by: Dr. Gang Bao, Ph.D., Advisor Dr. Mark Goodman, Ph.D. Department of Biomedical Engineering Department of Radiology and Imaging Georgia Institute of Technology and Emory Sciences University Emory University Dr. Yongjian Liu, Ph.D. Dr. Hui Mao, Ph.D. Department of Radiology Department of Radiology and Imaging Washington University School of Medicine Sciences Emory University Dr. Farzad Rahnema, Ph.D. Dr. W. Robert Taylor, MD, Ph.D. Department of Mechanical Engineering Department of Cardiology Georgia Institute of Technology Emory University, Georgia Institute of Technology and Atlanta VA Date Approved: July 29th, 2014 DEDICATION To loving memory of my father Bahram Hoshyar, my mother Nasrin and my brothers Yousef and Behnam. & My husband Ata iii ACKNOWLEDGEMENTS I am extremely grateful to my thesis advisor Professor Gang Bao for the opportunity to participate in this research. His patience and guidance as an advisor and mentor have been invaluable. I would like to thank the members of my thesis committee, Dr. Mark Goodman, Dr. Yongjian Liu, Dr. Hui Mao, Dr. Farzad Rahnema, and Dr. Robert Taylor for their time and instruction. To the past and present members of Bao Lab, thank you for the foundation you have built and for your help with this research. In particular, I would like to thank Dr. Sheng Tong and Dr. Sijian Hue for being available to answer my many coating questions. This work would have been much more difficult without Dr. Johaness Leisen’s help in performing MRI. I also like to thank Annie Zheng for her help with cell culture and microscopy. Also I like to thank Amy Tang for her support. I am grateful to Erin Kirshtein for her support and wonderful spirit. I also thank Dr. Charlie Glaus for his help in answering my conjugation questions. I thank Sally Gerrish for her help with career search. I also thank Glenda Johnson for her advise on graduate studies. I especially thank Dr. Wone Woo Seo for all his help and support at Wesley Woods. This dissertation would not be completed without Wone Woo’s help. I also thank the members of Dr. Goodman’s group, especially Dr. Voll for always being helpful. Also, I thank Mel Kemp, Larry Williams, and Eugene Malveaux for their help with biodistribution studies. Also, I thank Aaron Smith for his help with autoradiography. I am also thankful to Dr. Jon Nye for his help with PET imaging and teaching me image analysis. I also thank Margie Jones and Dr. Jaekun Park for her help with PET imaging. iv I especially thank members of Dr. Taylors group, Diana Weiss, Sarah Knight and Jane Titterington. Also, I thank Dr. Liu’s research group, Hannah and Debbie. I am grateful to Liya Wang for her help with preparing the 4T1 animal model. I also thank Dr. Ravi Bellamkonda for being a great mentor and his efforts in conducting the graduate leadership program. I also thank Dr. Garmestani for always being supportive and kind. I thank my undergraduate students, Needa Virani, Arsalan Saboori, and Samantha Gray for their outstanding work. I also thank Nassir Mokarram for his help and advice regarding chemistry and conjugation issues and for his friendship. Finally, I would like to thank my family for all their support during the past six years. I especially like to thank my husband Ata for his love, support and understanding. v TABLE OF CONTENTS DEDICATION................................................................................................................. III ACKNOWLEDGEMENTS ........................................................................................... IV LIST OF FIGURES ..................................................................................................... VIII LIST OF SYMBOLS AND ABBREVIATIONS ........................................................... X SUMMARY ..................................................................................................................... XI CHAPTER 1: DUAL MODALITY PET/MR CONTRAST AGENT .......................... 1 Nanoparticles for PET/MR Imaging ............................................................................... 1 SPIO Synthesis................................................................................................................ 3 SPIO Characterization .................................................................................................... 5 64Cu Radiolabeling, Characterization and Serum Stability............................................. 6 Discussion and Conclusion ............................................................................................. 9 References ..................................................................................................................... 11 CHAPTER 2: EFFECT OF SIZE ON NANOPARTICLE PHARMACOKINETICS AND BIODISTRIBUTION ............................................................................................ 13 Trends in vitro ........................................................................................................................... 14 Cellular Uptake .......................................................................................................................... 14 Active Targeting ........................................................................................................................ 18 Trends in vivo ............................................................................................................................ 20 Pharmacokinetics of 6nm and 14nm SPIOs .............................................................................. 24 Biodistribution studies of 6 nm and 14 nm SPIOs .................................................................... 27 Discussion and Conclusion ........................................................................................................ 32 References ................................................................................................................................. 33 Chapter 3: IN VIVO IMAGING OF EARLY STAGE ATHEROSCLEROTIC PLAQUES ........................................................................................................................ 38 Atherosclerosis .......................................................................................................................... 38 VCAM1 Targeting ..................................................................................................................... 39 Plaque Imaging .......................................................................................................................... 42 In Vitro Targeting Studies ......................................................................................................... 44 Phantom Studies ........................................................................................................................ 45 Carotid Ligation Model ............................................................................................................. 46 In vivo and Ex vivo imaging using DiR labeled SPIOs ............................................................ 47 vi In vivo PET/CT imaging using 64Cu-VINP-SPIOs ................................................................... 49 Discussion and Conclusion ........................................................................................................ 51 References ................................................................................................................................. 53 CHAPTER 4: TUMOR IMAGING .............................................................................. 55 In vivo imaging of 4T1 Tumor .................................................................................................. 56 Surface coating and functionalizing 64Cu-CD105 Targeted SPIOs ........................................... 60 Phantom Studies ........................................................................................................................ 64 Radiolabeling and characterization ........................................................................................... 65 4T1 Tumor Model ..................................................................................................................... 66 PET Imaging and Biodistribution studies of CD105 Targeted SPIOs....................................... 67 In vivo MR imaging using 64Cu-CD105-SPIOs ........................................................................ 70 Discussion and Conclusion ........................................................................................................ 71 References ................................................................................................................................. 74 CHAPTER 5: CONCLUSIONS AND FUTURE CHALLENGES ............................ 77 APPENDIX A: ................................................................................................................. 81 APPENDIX B: ................................................................................................................. 82 CURRICULUM VITA ..................................................................................................