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On the Development of Analytical Methodologies to Interrogate The Louisiana State University LSU Digital Commons LSU Doctoral Dissertations Graduate School 2015 On the Development of Analytical Methodologies to Interrogate the Lipid Dynamics and Phase Transition Resulting from the Reduction of Stimuli-responsive Vesicles James Edward Winter Louisiana State University and Agricultural and Mechanical College Follow this and additional works at: https://digitalcommons.lsu.edu/gradschool_dissertations Part of the Chemistry Commons Recommended Citation Winter, James Edward, "On the Development of Analytical Methodologies to Interrogate the Lipid Dynamics and Phase Transition Resulting from the Reduction of Stimuli-responsive Vesicles" (2015). LSU Doctoral Dissertations. 4015. https://digitalcommons.lsu.edu/gradschool_dissertations/4015 This Dissertation is brought to you for free and open access by the Graduate School at LSU Digital Commons. It has been accepted for inclusion in LSU Doctoral Dissertations by an authorized graduate school editor of LSU Digital Commons. For more information, please [email protected]. ON THE DEVELOPMENT OF ANALYTICAL METHODOLOGIES TO INTERROGATE THE LIPID DYNAMICS AND PHASE TRANSITION RESULTING FROM THE REDUCTION OF STIMULI-RESPONSIVE VESICLES A Dissertation Submitted to the Graduate Faculty of the Louisiana State University and Agricultural and Mechanical College in partial fulfillment of the requirements for the degree of Doctor of Philosophy in The Department of Chemistry by James Edward Winter B.S., The University of Georgia, 2010 A.S., Dalton State College, 2008 December 2015 This dissertation is dedicated to my parents: My Mom, Connie Winter My Dad, Larry Winter Thank you for your enduring love, support, and encouragement ii ACKNOWLEDGMENTS One of my favorite hobbies is backpacking deep in the wilderness. Often, mid- way through a long venture, when the mental and physical challenges are at their greatest, when it is cold, raining, and there is a centimeter of standing water in my hiking boots, I stop and ask myself why I voluntarily do this in my spare time. While the sense of self-preservation is motivating enough to keep trudging on, nature’s spectacle always offers reminder as to why. Hands down the best part of a long hike is its conclusion. This jubilation does not come from leaving the wilderness and returning to civilization; it stems from a sense of conquering achievement – the adversity overcome, the mountains climbed, and the distance traveled. It is a great feeling! As I reflect over the last 5 years of my doctorial experience, as much is the same; it too is a great feeling of accomplishment. I first want to especially thank Professor McCarley for opening his lab to me and being an excellent mentor over the years. When it came to selecting a research group, I wanted to make the most out of my time in graduate school and select a challenging research topic that I had very little knowledge about. I remember first meeting with Professor McCarley and being intimidated about the on-going research in his lab. Not having a firm background in organic chemistry or biology, this liposome project was what I was looking for, and it did not disappoint. I also want to thank Dr. Weldeghiorghis and Dr. Treleaven for their guidance, education, and expertise in the NMR facility at LSU. Dr. Treleaven aided in configuring the experimental setup for the 31P NMR liposomal phase studies in my research. He was also a mentor early on in my graduate years and had a positive impact on my scientific development. Moreover, the time spent working in the NMR faculty with both iii Dr. Weldeghiorghis and Dr. Treleaven afforded numerous opportunities where I was able to gain instrumental and experimental experience with these instruments. For this, I am most grateful. A special thanks to my fellow McCarley group members both past and present. This has been an amazing group of people to work with on a daily basis. Whenever there was a problem or an issue that needed attention, there was never any blaming nor was there a shortage of volunteers. I am also most appreciative of the organic chemists in the McCarley group for answering the countless synthetic chemistry questions and aiding me along the way. To the my post-docs both past and present – Dr. Martin Loew, Dr. Quinn Best, and Dr. Eli Mitran, thank you for training and instilling in me the proper analytical and organic lab techniques. To my colleagues in the Department of Chemistry at LSU – thank you for all that you do to make this department function on a daily basis. To my committee members – Dr. Gilman, Dr. Murray, and Dean’s representative Dr. Benton, thank you for taking your time to participate in both my general exam and thesis defense. And to my family – thank you for your unwavering love and support. iv TABLE OF CONTENTS ACKNOWLEDGMENTS……………………………………………….…………...………...iii LIST OF TABLES………………………………………………………………………….….vii LIST OF FIGURES……………………………………………………………………..…….viii LIST OF SCHEMES…………………………………………………………………............xiii LIST OF ABBREVIATIONS AND SYMBOLS……………………………………………...xiv ABSTRACT………………………………………………………………………….............xvii CHAPTER 1. INTRODUCTION……………………………..………………………………..1 1.1 Research Goals and Aims………………………………………………………….…1 1.2 The Nature of Lipids……………………………………………………….…………..4 1.2.1 Defining Aqueous Phospholipid Dispersions..…......…………………….…4 1.2.2 Factors Determining Phase Behavior……….……………………………….6 1.2.3 Curvature of Apposed Bilayers………..……………………………………...8 1.3 Liposome Drug Delivery Systems……………….………………………...………..11 1.4 Stimuli-responsive Liposomes…………………...………………………………....16 1.4.1 Open-circuit Stimuli…………..………………………………………………16 1.4.2 Closed-circuit Stimuli…………..………………….………………………....18 1.5. NAD(P)H:Quinone Oxidoreductase Type 1……………………..………………....20 1.6 Redox-triggered QPA-DOPE……………………………….…………………..........23 1.7 References…………………………………………………………………..………..24 CHAPTER 2. EXPERIMENTAL METHODS………………………………………...........48 2.1 Aqueous Media……………………………………………………………………….48 2.1.1 Buffer Preparation……………………………………………………...........48 2.1.2 Vapor Pressure Osmometry………………….……………………………..49 2.2 Liposome Preparation…………….…………………………………………...........50 2.2.1 Large Unilamellar Vesicles (LUVs)……….………………………………...51 2.2.2 Size-Exclusion Chromatography.…………….…………………………….52 2.2.3 Determining Lipid Concentration …………………………………………...53 2.3 Liposome Contents Release and Aggregation……………………………............55 2.4 Tb3+/DPA2 Fusion Assay…..………………………………………………………..57 2.4.1 Encapsulation Media………………………………………………………...58 2.4.2 Reverse Phase Vaporization..……………………………………………....58 2.4.3 Size-Exclusion Chromatography: Fusion Assay......................................59 2.4.4 Ca2+-induced Fusion…………………………………………………...........59 2.5 QPA-DOPE Synthesis…..………..…………………………………………………..60 2.6 QBr-DOPE Synthesis……………………………………………………….………...65 2.7 Physical Characterization of Liposomes…………………………………………...70 2.7.1 Dynamic Light Scattering……………………………………………...........70 2.7.2 Zeta Potential………………………………………………………………....70 2.7.3 Differential Scanning Calorimetry……………………………….................71 v 2.8 31P NMR Anisotropy………………………………………………….……………....72 2.8.1 Hot Buffer Hydration……………………………………………..……….….73 2.8.2 Giant Unilamellar Vesicle Harvesting…………………………...……….…74 2.8.3 NMR Experimental: Shigemi NMR Tube & {1H} 31P Spin-echo…………..74 2.9 References…………………………………………………………………………....75 CHAPTER 3. POLYMORPHIC PHASE STUDIES OF QPA-DOPE USING 31P NMR ANISOTROPY……….……………...........................................82 3.1 Origins of Phospholipid 31P NMR Lineshapes……..……………………………....82 3.2 Principles of 31P NMR Anisotropy………………………………………………..….84 3.3 Goals, Aims, and Objectives……………………………………………………..….85 3.4 Buffer Media……………………………………………………………………….….86 3.5 Method to Prepare QPA-DOPE GUVs…………………………………………..….87 3.6 31P NMR Anisotropy Results and Discussion………………………………….…..91 3.7 Conclusion………………………………………………………………………........95 3.8 References………………………………………………………………………..…..95 CHAPTER 4. A TRIGGERABLE RAPID CONTENTS RELEASE LIPOSOMAL SYSTEM BASED ON A REDOX-SENSITIVE QPA-DOPE:POPE LIPID MIXTURE…………….……………...……………………….………101 4.1 Introduction…………..………………………………………………………...……101 4.2 Results…...…………………………………………………………………………..104 4.3 Discussion……………………………………………………………………...……112 4.4 Conclusion………………………………………………………………………......117 4.5 References…………………………………………………………………………..118 CHAPTER 5. SUMMARY, CONCLUSIONS, AND OUTLOOK…………………….…..122 5.1 Summary and Conclusions……………………………………………………...…122 5.2 Outlook…....……………………………………………………………………..…..125 5.2.1 New Class of PE-functionalized Lipids.…………………………………...125 5.2.2 Redox-triggered Liposomal Nanoreactors……………..…………………126 5.2.3 Second Harmonic Generation Studies………………………..…………..130 5.3 References………………………………………………………………………..…135 APPENDIX A LETTERS OF PERMISSION………….………………………………………...…137 . B LIPID CONCENTRATION ASSAYS………………….…………………………..140 C 1H NMR, 13C NMR, AND ESI-MS……..................……………………………….142 D DLS AND ZETA POTENTIAL..…………………………………………………….156 E QPA-POPE…………………………………………………………………………...158 VITA…………………..……………………...……………………………………...……….159 vi LIST OF TABLES Table 1.1 Listed are the liposomal drug delivery formulations currently on the market or at various phases of development. In the adjacent column of the liposomal system’s name is its corresponding treatment application…………………………………………………..........14 Table 4.1 The time required for 50% of the encapsulated contents to release (t50), percent of total content release for the various QPA- DOPE vesicle systems at 40 °C, and average liposome diameter….………….106 Table 5.1 Kinetic parameters
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