Host-Guest Interaction Mediated Pluronic F127 Based Hydrogel for Delivery of Therapeutic Agents

Abstract

학위논문 (석사)-- 서울대학교 대학원 : 공과대학 재료공학부, 2018. 2. 안철희.Poloxamer composed of poly(ethylene oxide)- poly(propylene oxide)- poly(ethylene oxide) triblock copolymer which is called Pluronic F127 is representative material for showing reversible sol-gel transition by temperature change. This behavior is achieved by micelle packing mechanism above critical gelation concentration. Micelle structure is obtained around 15 ℃ and more micelles are formed as temperature increases because each block has different low critical solution temperature. This thermoreversible hydrogel has attractive characteristics for therapeutic agent delivery carriers due to its high water contents and similar mechanical property like the extracellular matrix. However, it has limitation for using in clinical application due to its low stability. To overcome the critical drawback of Pluronic F127 hydrogel, the host-guest interaction was utilized to enhance packing ability of micelles. Due to strong host-guest interaction, it was possible to achieve highly improved mechanical stability. However, the viscosity of the blended solution was too high for injection due to existing strong host-guest interaction at injection condition (at 4 ℃). Thus, the system was still hard to deliver therapeutic proteins and cells. To maintain long-term stability of hydrogel and improve injection ability, multi-guest molecules were conjugated at the end of Pluronic F127 for strengthening the micelle packing while reducing the amount of each polymer needed. Because of increased host-guest complex at a reduced concentration, critical gelation concentration of blended solution decreased comparing with conventional Pluronic F127 hydrogel and mono guest conjugated F127 hydrogel system. As a result, the viscosity of multi-guest conjugated F127 / CDP blended solution at the injectable condition largely decreased comparing with the conventional method and the high stability was maintained in the physiological condition. In addition, this host-guest interaction based gel system enabled affinity based protein release. Host molecule modified protein showed sustained protein release profile in this system. Consequently, multi-guest conjugated Pluronic F127 hydrogel which has overcome its limitations while maintaining existing merits is expected to be used for various biomedical application1. Introduction 1 2. Experiments 5 2.1. Materials 5 2.2. Synthetic procedure of multi-guest - Pluronic F127 6 2.2.1 Activation of Pluronic F127 with p-NPC (F127-NPC) 6 2.2.2 Conjugation of Serinol with F127-NPC (F127-Di) 7 2.2.3 Activation of F127-Di with p-NPC (F127-Di-NPC) 8 2.2.4 Conjugation of 1-adamantane (Ad) methylamine with F127-Di-NPC 8 2.2.5 Conjugation of Tris with F127-NPC (F127-Tri) 9 2.2.6 Activation of F127-Tri with p-NPC (F127-Tri-NPC) 10 2.2.7 Conjugation of 1-adamantane (Ad) methylamine with F127-Tri-NPC 11 2.3. Synthesis of gelatin-CD and gelatin-Ad 12 2.4. Phase Diagram of Sol-Gel Transition. 12 2.5. Size Analysis 13 2.6. Rheological studies 13 2.7. In vitro Gel Dissolution Rate 14 2.8. In vitro Protein Release Profile 15 2.9. Instruments 15 3. Results and Discussion 16 3.1. Synthesis and characterization of multi-guest conjugated Pluronic F127 (F127-Di-Ad and F127-Tri-Ad) 16 3.2. Phase Diagram of Sol-Gel Transition. 20 3.3. Size Analysis 24 3.4. Viscosity Comparison 26 3.5. In vitro Gel Dissolution Rate 29 3.6. In vitro Protein Release Profile 31 4. Conclusion 34 5. References 35Maste