Affinity-Based Delivery of Retinoids
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AFFINITY-BASED DELIVERY OF RETINOIDS STEVEN MICHAEL VESOLE Submitted in partial fulfillment of the requirements For the degree of Master of Science Department of Biomedical Engineering CASE WESTERN RESERVE UNIVERSITY August, 2011 CASE WESTERN RESERVE UNIVERSITY SCHOOL OF GRADUATE STUDIES We hereby approve the thesis/dissertation of __Steven Michael Vesole_______________________ candidate for the _MS Engineering______________degree *. (signed)______Horst von Recum, Ph.D.___________ (Chair of the Committee) _______Zheng-Rong Lu, Ph.D.______________________ _______Erin Lavik, Sc.D.___________________________ ________________________________________________ ________________________________________________ ________________________________________________ (date) _______June, 30th 2011_______________ *We also certify that written approval has been obtained for any proprietary material contained therein. I grant to Case Western Reserve University the right to use this work, irrespective of any copyright, for the University’s own purposes without cost to the University or to its students, agents and employees, I further agree that the University may reproduce and provide single copies of the work, in any format other than in or from microforms, to the public for the cost of reproduction. __________STEVEN M VESOLE_______________________ (sign) Table of Contents List of Tables ......................................................................................................................2 List of Figures .....................................................................................................................3 Preface .................................................................................................................................7 Acknowledgments ..............................................................................................................8 Abstract ...............................................................................................................................9 Chapter 1 Background ....................................................................................................10 Age-Related Macular Degeneration ...............................................................................10 Retinoids .........................................................................................................................13 Drug Delivery Technologies/ Eye Delivery ...................................................................17 Cyclodextrins/Cyclodextrin Polymers/ with Retinoids ..................................................24 Chapter 2 CDP Hydrogels: Synthesis and Mechanical Properties .............................36 Results/Discussion .........................................................................................................42 Chapter 3 CDP Hydrogels: Understanding Drug Loading .........................................58 Results/Discussion .........................................................................................................60 Chapter 4 CDP Hydrogels: Understanding and Predicting Drug Interactions .........68 Results/Discussion .........................................................................................................71 Chapter 5 Retinoid Delivery with 1st Generation Cyclodextrin Hydrogel .................88 Results/Discussion .........................................................................................................90 Chapter 6 Retinoid Delivery with Cyclodextrin/Dextran Hydrogel Blends .............100 Results/Discussion .......................................................................................................106 Chapter 7 Retinoid Delivery with BSA/Cyclodextrin Hybrid Hydrogels .................119 Results/Discussion .......................................................................................................123 Chapter 8 Conclusions/Future Direction .....................................................................139 Retinoids and Lasting Impact .......................................................................................148 Bibliography ..................................................................................................................149 1 List of Tables Table # Page # Description Table 1 14 Examples of naturally occurring retinoids Table 2 20 Stakeholders in translational science and their objectives Table 3 23 Biodegradable and non-biodegradable ocular delivery platforms Table 4 24 Ocular delivery technologies and duration of release Table 5 27 Common cyclodextrins and several key properties Table 6 38 List of samples for analysis of gelation behavior Table 7 39 List of polymer blends in terms of weight percentage Table 8 46 Gelation time and storage modulus from isothermal cure Table 9 50 Density and polymer volume fraction as a function of CDP % Table 10 51 Parameters from log-log plot of shear modulus versus frequency Table 11 54 Network parameters for polymer blends Table 12 59 Rhodamine loading study sample list Table 13 64 Slope of gray level transition regime at 24 and 48 hours Table 14 73 Change in emission signal compared to DMSO control Table 15 75 Free energy of binding from simulation and experimental values Table 16 76 Free energy of binding from surrogate retinoid and therapeutic Table 17 97 Summary of fit parameters for two-phase release Table 18 98 Summary of pharmacokinetic parameters including half-life Table 19 102 List of polymer blends in terms of weight percentage Table 20 105 DSC method for analyzing dextran and CDP gels Table 21 120 Various compositions of BSA/CDP hybrid gels Table 22 137 Double exponential fit parameters for BSA/CDP gels Table 23 148 Retinoids that are used in other clinical applications 2 List of Figures Figure # Page # Description Figure 1 12 Graphical depiction of dry AMD disease progression Figure 2 14 Basic structure of a retinoid Figure 3 15 Graphical representation of the cone-specific visual cycle Figure 4 18 Questions that typically arise during drug delivery design Figure 5 19 How to evaluate a delivery technology Figure 6 25 Affinity delivery vs. typical first-order release Figure 7 26 Structure of beta-cyclodextrin Figure 8 28 Hydrophobic cavity of CD for loading and release of drug Figure 9 31 Structure of BCD crosslinked with epichlorohydrin Figure 10 32 Structure of CDP crosslinked with EGDE Figure 11 45 Synthesis procedure for CDP hydrogel Figure 12 45 Urethane bond formation during synthesis Figure 13 46 Drug loading process after network formation Figure 14 47 Gelation time and storage modulus of CDP Figure 15 48 Gelation time and storage modulus of Dextran Figure 16 49 Retinol’s hydroxyl shielded by CD during synthesis Figure 17 50 Swelling equilibrium versus CDP content Figure 18 52 Log-log plot of shear modulus versus frequency Figure 19 53 Tan delta as a function of frequency Figure 20 55 Linear regression for χ parameter versus calculated values Figure 21 56 Strain sweep of CDP/Dextran blended gels Figure 22 56 Stress relaxation for CDP/Dextran blended gels Figure 23 61 Rhodamine B dye front through CDP and Dextran Hydrogels 3 Figure 24 61 Figure 23 with black and white filter applied Figure 25 63 Gray level as a function of distance along gel during load Figure 26 63 Gray level difference between 3min and 24 hours of loading Figure 27 65 Gray level transition region slope calculation at 24,48 hours Figure 28 66 Full time course for loading a gel with Rhodamine B Figure 29 72 Emissions scan for various polymers doped with retinol Figure 30 74 Emissions signal versus temperature with different polymers Figure 31 76 Linear regression of experimental values versus simulation Figure 32 78 Effect of BCDP concentration on retinol emissions Figure 33 78 Effect of retinol emissions versus temperature Figure 34 80 Double reciprocal plot to determine equilibrium constant Figure 35 81 Arrhenius plot of ln(K) versus 1/T Figure 36 82 Boundary conditions for drug delivery system Figure 37 85 Predicted release from dextran hydrogel Figure 38 85 Predicted release from CDP hydrogel Figure 39 92 Model of BSA’s hydrophobic domains Figure 40 93 BSA fluorescence is quenched by retinol presence Figure 41 94 Stern-Volmer plot for retinol quenching Figure 42 95 Retinol release from 1st Generation BCDP and Dextran Gels Figure 43 96 Diagram of biphasic release process Figure 44 97 Fitted release profile based on biphasic model Figure 45 106 Loading dependence related to loading sink concentration Figure 46 107 CDP/Dextran blended gels after loading Figure 47 107 Drug loading percent based on mass after loading Figure 48 108 Drug loading percent based on drug extracted and released 4 Figure 49 109 TGA curves for CDP hydrogel +/- retinol Figure 50 109 TGA curves for dextran hydrogel +/- retinol Figure 51 111 DSC thermogram for bulk retinol Figure 52 112 DSC thermogram for CDP hydrogel +/- retinol Figure 53 112 DSC thermogram for dextran hydrogel +/- retinol Figure 54 113 Cumulative release from CDP/Dextran blended gels Figure 55 114 Logarithmic fit for release from CDP/Dextran blended gels Figure 56 115 Calibration curve based on stoichiometric ratios of BSA:drug Figure 57 116 Distribution of data in terms of BSA:drug ratio Figure 58 117 SDS-PAGE of BSA in release medium after release Figure 59 124 Schematic of BSA/CDP crosslinked gel Figure 60 125 CDP/BSA hybrid gels at swelling equilibrium Figure 61 126 Simulation image of Evan’s Blue dye with BCD Figure 62 127 Calibration of Evan’s Blue dye in