Dynamic Contrast-Enhanced Magnetic Resonance Imaging & Fluorescence Microscopy of Tumor Microvascular Permeability

Dynamic Contrast-Enhanced Magnetic Resonance Imaging & Fluorescence Microscopy of Tumor Microvascular Permeability Item Type text; Electronic Dissertation Authors Jennings, Dominique Louise Publisher The University of Arizona. Rights Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author. Download date 03/10/2021 18:57:45 Link to Item http://hdl.handle.net/10150/193555 DYNAMIC CONTRAST-ENHANCED MAGNETIC RESONANCE IMAGING & FLUORESCENCE MICROSCOPY OF TUMOR MICROVASCULAR PERMEABILITY by Dominique Louise Jennings _____________________ A Dissertation Submitted to the Faculty of the DEPARTMENT OF BIOMEDICAL ENGINEERING In Partial Fulfillment of the Requirements For the Degree of DOCTOR OF PHILOSOPHY In the Graduate College THE UNIVERSITY OF ARIZONA 2008 2 THE UNIVERSITY OF ARIZONA GRADUATE COLLEGE As members of the Dissertation Committee, we certify that we have read the dissertation prepared by: Dominique L. Jennings entitled: Dynamic Contrast-Enhanced Magnetic Resonance Imaging & Fluorescence Microscopy of Tumor Microvascular Permeability and recommend that it be accepted as fulfilling the dissertation requirement for the Degree of Doctor of Philosophy _______________________________________________________________________ Date: 01/16/08 Robert J. Gillies _______________________________________________________________________ Date: 01/16/08 Theodore P. Trouard _______________________________________________________________________ Date: 01/16/08 Natarajan Raghunand _______________________________________________________________________ Date: 01/16/08 Robert A. Gatenby Final approval and acceptance of this dissertation is contingent upon the candidate’s submission of the final copies of the dissertation to the Graduate College. I hereby certify that I have read this dissertation prepared under my direction and recommend that it be accepted as fulfilling the dissertation requirement. ________________________________________________ Date: 01/16/08 Dissertation Director: Robert J. Gillies ________________________________________________ Date: 01/16/08 Co-Dissertation Director: Theodore P. Trouard 3 STATEMENT BY AUTHOR This dissertation has been submitted in partial fulfillment of requirements for an advanced degree at the University of Arizona and is deposited in the University Library to be made available to borrowers under rules of the Library. Brief quotations from this dissertation are allowable without special permission, provided that accurate acknowledgment of source is made. Requests for permission for extended quotation from or reproduction of this manuscript in whole or in part may be granted by the head of the major department or the Dean of the Graduate College when in his or her judgment the proposed use of the material is in the interests of scholarship. In all other instances, however, permission must be obtained from the author. SIGNED: Dominique L. Jennings 4 ACKNOWLEDGMENTS I would like to thank my mentor and sole collegiate advisor for his patience, mentorship, and for training me to be independent, the most valuable lesson I learned in academic research. Through his training, I have learned to persevere in spite of disappointing and unexpected experimental results and appreciate those that were positive, but most importantly to “treat those two imposters just the same” ( §). I would like to thank another close mentor, Natarajan Raghunand, for endlessly encouraging me to understand more and to be a better student. Despite my fears and frustration with concepts such as transcytolemmal water exchange, the challenge of doing so has elevated my standard of expectations for myself and the scientific method. I would like to attribute my success with the window chamber experiments to Bethany Skovan for her meticuolous and tireless efforts to transform the window chamber preparation into the success that it is today. The experiments that comprise this dissertation would not have been possible without her surgical talent. I would to thank my professor and mentor, Ted Trouard, for his enthusiasm patience for teaching NMR and especially MRI, making it an exciting concept to learn. I would also like to thank him for showing us that it was alright to be confused, to ask more questions when you are because an attempt to understand the lesson is a contribution to that lesson. As one of the smartest scientists I know, I have taken this lesson in earnest. There are many people that contributed to my technical learning of NMR and MRI. I would like to thank Constantine Job for long tutorials on NMR/MRI, scanner hardware and coil electronics, but mostly for his friendship. I would also like to thank Jingyu Guo for his patience and willingness to teach an undergraduate Biochemistry student the basic, functional aspects of running an animal research spectrometer. Non-academic thanks go to my family for their support, especially my brother for convincing me to go to college and become more than I thought I deserved to be, and my mother for always helping and supporting me with her unconditional love. Finally, I have to thank my husband for his patience, understanding, love, but most of all for his contribution to the scientist I am today and the accomplishments I could not have made without this support. I would never have come this far without him. § Rudyard Kipling (1895). If—. In Rewards and Fairies . 5 DEDICATION Dedicated to my husband, Nathaniel D. Kirkpatrick, Ph.D. 6 TABLE OF CONTENTS 1. LIST OF ILLUSTRATIONS ........................................................................................ 9 2. LIST OF TABLES ...................................................................................................... 11 3. ABSTRACT................................................................................................................ 12 4. CHAPTER 1................................................................................................................ 13 Section 1 1.1. Defining Vascular Permeability and Perfusion................................................... 13 1.2. Macrocirculation – Overview.............................................................................. 13 1.2.1. Morphology............................................................................................... 13 1.2.2. Vessel Regulation of Flow........................................................................ 14 1.3. Capillary Microcirculation .................................................................................. 16 1.3.1. Passive Capillary Transport ...................................................................... 18 1.4. Angiogenesis ....................................................................................................... 19 1.4.1. Molecular Mechanisms of Angiogenesis.................................................. 21 1.4.2. Microcirculatory Assays ........................................................................... 23 1.4.3. Matrix Implant Assays.............................................................................. 25 1.4.4. Ex Vivo Assays.......................................................................................... 26 1.5. Tumor angiogenesis ............................................................................................ 26 1.6. Using Imaging to Estimate Microvascular Permeability .................................... 28 Section 2 2.1. Imaging the Tumor Microvasculature: Survey of Methods................................. 30 2.2. Measurement of Hemodynamics with PET/SPECT ........................................... 30 2.2.1. Response to Antivascular Therapy ............................................................ 31 2.2.2. Response to Cytotoxic Therapy................................................................. 32 2.2.3. Kinetic Modeling of PET/SPECT Data ..................................................... 35 2.3. Measurement of Hemodynamics with CT ........................................................... 36 2.3.1. Kinetic Modeling of Perfusion CT Data.................................................... 39 2.4. Measurement of Hemodynamics with Ultrasound............................................... 40 7 2.4.1. Modeling of Perfusion Ultrasound Data.................................................... 44 2.5. Measurement of Hemodynamics with Optical Imaging ...................................... 45 2.5.1. Kinetic Modeling of Dynamic Optical Imaging Data................................ 48 2.6. Nuclear Magnetic Resonance............................................................................... 49 2.7. Magnetic Resonance Imaging.............................................................................. 56 2.8. Measurement of Hemodynamics with DCE-MRI................................................ 58 2.8.1. MRI Contrast Agents ................................................................................. 59 2.8.2. Kinetic Modeling of Dynamic-Contrast Enhanced MRI Data .................. 60 2.8.3. Transcytolemmal Water Exchange............................................................ 63 Section 3 3.1. Antiangiogenic & Antivascular Therapies........................................................... 72 3.2. Imaging Response to Antivascular vs. Antiangiogenic Therapies......................

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