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Pointsource Delivery of Singlet Oxygen, Sensitizer and Nitrosamine Drugs City University of New York (CUNY) CUNY Academic Works All Dissertations, Theses, and Capstone Projects Dissertations, Theses, and Capstone Projects 6-2016 Photooxidation Chemistry and Photodynamic Therapy: Pointsource Delivery of Singlet Oxygen, Sensitizer and Nitrosamine Drugs Ashwini Anil Ghogare Graduate Center, City University of New York How does access to this work benefit ou?y Let us know! More information about this work at: https://academicworks.cuny.edu/gc_etds/1245 Discover additional works at: https://academicworks.cuny.edu This work is made publicly available by the City University of New York (CUNY). Contact: [email protected] PHOTOOXIDATION CHEMISTRY AND PHOTODYNAMIC THERAPY: POINTSOURCE DELIVERY OF SINGLET OXYGEN, SENSITIZER AND NITROSAMINE DRUGS by ASHWINI ANIL GHOGARE A dissertation submitted to the Graduate Faculty in Chemistry in partial fulfillment of the requirements for the degree of Doctor of Philosophy, The City University of New York 2016 ii 2016 ASHWINI ANIL GHOGARE All Rights Reserved iii This manuscript has been read and accepted for the Graduate Faculty in Chemistry in satisfaction of the dissertation requirement for the degree of Doctor of Philosophy. PROFESSOR ALEXANDER GREER Date Chair of Examining Committee April 7, 2016 PROFESSOR BRIAN R. GIBNEY Date Executive Officer PROFESSOR WAYNE W. HARDING Supervision Committee PROFESSOR DAVID R. MOOTOO Supervision Committee THE CITY UNIVERSITY OF NEW YORK iv ABSTRACT Photooxidation Chemistry and Photodynamic Therapy: Pointsource Delivery of Singlet Oxygen, Sensitizer and Nitrosamine Drugs by Ashwini Anil Ghogare Advisor: Professor Alexander Greer Eradication of residual tumor cells that are directly adjacent to vital tissue is a daunting challenge to surgeons. Because the field needs advances in intraoperative settings and a means for high-precision delivery of singlet oxygen for photodynamic therapy (PDT) of cancers, this dissertation outlines the development and application of a “pointsource” fiber optic device. The device offers highly localized and simultaneous delivery of sensitizer drug, light, and oxygen (components necessary for PDT) for cancer cell eradication in-vitro and in-vivo. The following chapters describe (a) the photokilling activity and precision of pointsource PDT in monolayer ovarian and brain cancer cells in-vitro by creating a halo of singlet oxygen, (b) minimal biomaterial fouling on the pace of sensitizer drug photorelease into in-vivo tumors of the head and neck cancer, and (c) synthesis of PEGylated pheophorbide sensitizers to enhance their bio-availability and uptake in cancer cells. (d) With the view of delivering nitrosamine drugs alongside singlet oxygen for dual chemo-photodynamic therapy, the photooxidation mechanism in N-nitrosamines was studied. 18O-isotopic labelling, photochemistry, tandem mass spectrometry and DFT calculations were utilized and an 18O label scrambling into aromatic but not aliphatic N-nitrosamine drugs from v 18 molecular O2, was discovered. The oxygen atom exchange mechanism was proposed to occur by nitrosoperoxy intermediates and might provide a clue to new factors significant in nitrosamine 1 phototoxicity. (e) Lastly, a review of the literature is presented on using singlet oxygen ( O2) to synthesize natural products and drugs that intends to draw a logical link between flow and batch 1 reactions in the current state of O2 in synthesis. vi DEDICATION This dissertation is dedicated to my loving parents, Sheela and Anil Ghogare, my beloved sisters, Prachi and Manasi Ghogare, and my husband, Mahendran Adaickapillai. I am truly blessed to have all of you in my life. vii ACKNOWLEDGMENTS This doctoral dissertation was made possible with the contribution, mentorship and support from many people. First and foremost, I want to express my immense appreciation and gratitude to my advisor, Dr. Alexander Greer. He has been a good friend and a great mentor throughout the course of my doctoral research. His strong belief in my potential and his constant encouragement, motivated me to achieve my goals. He introduced me to the field of photochemistry and photobiology and gave me the freedom to explore my scientific curiosity which were key in shaping me as a scientific researcher. I have been inspired by his perseverance and passion for exploring new scientific ideas and I want to thank him for giving me the opportunity to work on many interdisciplinary research projects under his guidance. I want to thank members of my thesis committee, Dr. Wayne W. Harding and Dr. David R. Mootoo for their guidance and insightful comments during the committee meetings which helped to widen the scope of my research. I am grateful to many friends and colleagues, who made my time enjoyable at Brooklyn College and the Graduate Center. The past and present members of the Greer group and other groups in the Chemistry Department have contributed immensely to my personal and professional growth and have been a great source of support throughout my doctoral research. I was fortunate to work with some great collaborators during the course of my dissertation. I want to thank Dr. Imran Rizvi and Dr. Tayyaba Hasan for giving me the opportunity to work in their laboratory at the Wellman Center for Photomedicine, Massachusetts General Hospital, Boston. It was a very enriching experience for me as a doctoral student in organic chemistry to learn new techniques in cancer biology and photodynamic therapy. viii I would like to thank Joann M. Miller, Dr. Keith A. Cengel and Dr. Theresa M. Busch from Department of Radiation Oncology, University of Pennsylvania, PA for their efforts in developing head and neck cancer model in mice and conducting all the in-vivo procedures. I would also like to thank Dr. Bikash Mondal and Dr. Alan M. Lyons from the Department of Chemistry, College of Staten Island, CUNY for their efforts with XPS analysis of proteins on silica surface. I would like to thank Dr. Marilene Silva Oliveira, Fernanda Manso Prado and Dr. Paolo Di Mascio from Departamento de Bioquímica, Instituto de Química, Universidade de Sao Paulo, Sao Paulo for their collaborative efforts in the HPLC-MS/MS and HRMS analysis, and Dr. Edyta M. Greer from Department of Natural Sciences, Baruch College, CUNY for the computational calculations, on nitrosamine compounds. I gratefully acknowledge the generous financial support through the CUNY Science Scholarship 2010-2015 and Doctoral Dissertation Year Award 2015-2016 from the Graduate Center of the City University of New York. This dissertation was also supported by the grants from National Institute of Health (NIH) and National Science Foundation (NSF). Finally I want to thank the most important people in my life, my family. They have supported me and encouraged me during the challenges of graduate school and throughout my life. Their unwavering faith and confidence in my abilities have inspired me to strive towards fulfilling my dreams. Especially my dad, who motivated me to pursue doctoral studies and Dr. Mahendran Adaickapillai who helped me to complete this endeavour in innumerous ways. Thank you very much! ix TABLE OF CONTENTS Page TITLE i APPROVAL PAGE iii ABSTRACT iv DEDICATION vi ACKNOWLEDGEMENT vii TABLE OF CONTENTS ix LIST OF SYMBOLS AND ABBREVIATIONS xv LIST OF FIGURES xix LIST OF SCHEMES xxiv LIST OF TABLES xxix Chapter 1. Introduction 1.1 Photooxidation Chemistry and Photodynamic Therapy (PDT) 1 1.2 Sections in the Thesis 3 1.3 References 5 Chapter 2. “Pointsource” Delivery of a Photosensitizer Drug and Singlet Oxygen: Eradication of Glioma Cells In-vitro 2.1 Introduction 7 2.2 Results and Discussion 9 2.2.1 Cell Phototoxicity and Sensitizer Uptake 9 x 2.2.2 Course of the Sensitizer Drug Photorelease in Phosphate 11 Buffered Saline (PBS) 2.2.3 Fiber Tip-Guided Sensitizer Delivery for Cell Killing in 12 Discrete Locations 2.2.4 “Lengthening” the Toxic Radius of Singlet Oxygen 13 2.2.5 Mechanism 15 2.3 Conclusion 16 2.4 Experimental Section 17 2.4.1 Materials and Methods 17 2.4.2 Device Fabrication and Instruments 18 2.4.3 Sensitizer Photorelease in Phosphate Buffered Saline (PBS) 19 2.4.4 Cellular Uptake in U87 MG Cell Monolayer 20 2.4.5 Phototoxicity of Pyropheoporbide-a in U87 MG Cell 21 Monolayer 2.4.6 Treatment Procedure 21 2.4.7 Sources of Error 22 2.5 References 23 Chapter 3. Fluorinated PDT Device Tips and Their Resistance to Fouling for In- vivo Sensitizer Release 3.1 Introduction 25 3.2 Results 27 3.2.1 Effects of Biofouling on Device Tip Sensitizer Release 28 3.2.2 Effect of Adsorption of Cellular Material 31 xi 3.3 Discussion 34 3.4 Conclusion 36 3.5 Experimental Section 36 3.5.1 Materials and Methods 36 3.5.2 Sensitizer Photorelease Studies 37 3.5.3 BCA Studies 38 3.5.4 XPS Studies 39 3.6 References 39 Chapter 4. Synthesis of an Poly(ethylene glycol) Galloyl Sensitizer Tip for a Pointsource Photodynamic Device 4.1 Introduction 42 4.2 Results and Discussion 44 4.2.1 Sensitizer Design and Solubility 44 4.2.2 Synthesis 45 4.2.3 Structural Assignments 47 4.2.4 Comparative Analysis 50 4.3 Conclusion 52 4.4 Experimental Section 53 4.4.1 Computations 53 4.4.2 Materials and Methods 53 4.4.3 Synthesis of TriPEG-galloyl (8) 54 4.4.4 Synthesis of TriPEG-galloyl-ether-31-pyropheophorbide Methyl 55 Ester (10) xii 4.4.5 Synthesis of TriPEG-galloyl-ether-31-pyropheophorbide 56 Carboxylic Acid (11) 4.4.6 Synthesis of TriPEG-galloyl-ether-31-pyropheophorbide-(Z)- 57 alkene Ester (13) 4.4.7 TriPEG-galloyl Pheophorbide Modified Fluorinated Silica (1) 58 4.4.8 Hydrolytic Stability 58 4.5
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