兩親性嵌段共聚物之原位成膠性質於細胞移植載體與藥物緩釋系統之應用：機制與優化研究

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研究生：	林修兆 Lin, Hsiu-Chao
論文名稱：	兩親性嵌段共聚物之原位成膠性質於細胞移植載體與藥物緩釋系統之應用：機制與優化研究 The Applications of Amphiphilic Block-copolymer In Situ Gelation for Transplanted Cell Scaffold and Sustained-release Systems — Mechanism and Optimization Study
指導教授：	朱一民 Chu, I-Ming
口試委員:	莊峻鍠 Juang, Jyuhn-Huarng 陳志平 Chen, Jr-Ping 孫一明 Sun, I-Ming 駱俊良 Lo, Chun-Liang
學位類別：	博士 Doctor
系所名稱：	工學院 - 化學工程學系 Department of Chemical Engineering
論文出版年：	2019
畢業學年度：	108
語文別：	英文
論文頁數：	110
中文關鍵詞：	溫度敏感型胺基酸水膠、原位成膠、胰島素、阿黴素、血管內皮生長因子、他克莫司
外文關鍵詞：	thermosensitive hydrogel, in situ gelation, insulin, vascular endothelial growth factor (VEGF), doxorubicin (DOX), tacrolimus (FK506)
相關次數：	點閱：1 下載：0
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本研究探討可原位成膠之溫度敏感型胺基酸水膠，藉由調整親疏水鏈段結構比例，並以帶正負電荷胺基酸分子修飾後，分析其成膠性質與機制以及應用於細胞骨架或長期藥物釋放之潛力。甲氧基化聚乙二醇-聚左旋丙胺酸[methoxy-poly(ethylene glycol)-poly(ʟ-alanine), mPEG-P(Ala)]為一已知溫度敏感型胺基酸水膠，利用mPEG-NH2和N-carboxy anhydride ʟ-alanine (NCA-alanine)開環聚合反應合成，再以N-carboxyl anhydride β-benzyl ʟ-aspartate/ ʟ-lysine開環聚合於mPEG-P(Ala)在末端進行修飾，分別自末端接上天門冬胺酸(ʟ-aspartate)與離胺酸(ʟ-lysine)並去除保護基，形成甲氧基化聚乙二醇-聚左旋丙胺酸-聚左旋天門冬胺酸[methoxy-poly(ethylene glycol)-poly(ʟ-alanine)-poly(ʟ-aspartate), mPEG-P(Ala)-Asp]與甲氧基化聚乙二醇-聚左旋丙胺酸-聚離胺酸[methoxy-poly(ethylene glycol)-poly(ʟ-alanine)-poly(ʟ-lysine), mPEG-P(Ala)-Lys]水膠，並依此進行各階段研究。
將於第一章節對於相關研究文獻討論；第二章節將探討所合成之高分子，以1H與13C核磁共振光譜儀、傅立葉轉換反射式紅外線光譜儀、凝膠滲透層析儀、流變儀、圓二色光譜儀、掃描式電子顯微鏡與穿透式電子顯微鏡分析，建立胺基酸水膠其各種性質及其成膠機制，此外，更進一步探討體外細胞毒性測試、生物相容性與水膠降解特性，以及作為藥物載體，釋放大分子蛋白質或包覆親/疏水性小分子藥物阿黴素(Doxorubicin, DOX)之可能；第三章節將進一步將水膠混合MIN6 β cell line，觀察其作為細胞支架之生物相容性與所包覆的MIN6 cells胰島素分泌功能；第四章將疏水型抗排斥藥物他克莫司(Tacrolimus, FK506)作為標的藥物，探討混合式胺基酸水膠與其藥物包覆及持續釋放情形。最後一章節為本研究之結論，將進一步比較在mPEG-P(Ala)的尾端修飾正、負電荷後，作為細胞骨架與藥物載體時之表現。本研究期望開發及改善胺基酸水膠，立基於具有原位成膠、良好的生物相容性、降解性等特性，以成為有優勢的細胞骨架或有潛力於局部的藥物治療之應用。

The objectives of this study are to discuss the thermoresponsive polypeptide hydrogel properties, the potential of in situ gelation in sustained drug delivery and cells scaffold. Methoxy-poly (ethylene glycol)-poly (ʟ-alanine), mPEG-P(Ala) is a well-known thermoresponsive polypeptide hydrogel. The block copolymer was synthesized through mPEG-NH2 and N-carboxy anhydride-alanine (NCA-ʟ-alanine) ring-opening polymerization. Afterwards, using N-carboxyl anhydride β-benzyl ʟ-aspartate/ ʟ-lysine through ring-opening polymerization again and removal of the benzyl protecting groups to form the hydrogel, we had two kinds of hydrogel based on the previous copolymer structure, methoxy-poly(ethylene glycol)-poly(ʟ-alanine)-poly(ʟ-aspartate), mPEG-P(Ala)-Asp and methoxy-poly(ethylene glycol)-poly(ʟ-alanine)-poly(ʟ-lysine), mPEG-P(Ala)-Lys. Therefore, we have synthesized a series of mPEG-P(Ala) diblock copolymers, mPEG-P(Ala)-Asp and mPEG-P(Ala)-Lys triblock copolymers, and investigated the hydrophilic/ hydrophobic block length effect on the secondary structure influencing the nanostructure of the self-assembled amphiphilic copolymers, the thermosensitivity of the hydrogels in aqueous solution.
The chapter I is a literature review regarding the field of hydrogels. After that, we explored the physicochemical properties of the copolymers in solubilized and hydrogel forms were studied in terms of their assembly and transition in response to temperature changes. Next, the researches were focused on demonstrating non-toxicity, biocompatibility, and biodegradability with 293T cells encapsulated in the hydrogel. Furthermore, we observed hydrogel as MIN6 cells scaffold and insulin responded to glucose. In order to enhance angiogenesis potential, we used hydrogel containing vascular endothelial growth factor (VEGF) and evaluated its release upon incorporation.
On the other hand, we discussed the regulation of drug release rate and depot potential of the different kinds of hydrogels. Bovine serum albumin (BSA), doxorubicin (DOX) and tacrolimus (FK506) were model molecules which were encapsulated in the hydrogels. We proposed the well use of a thermosensitive mPEG-peptide hydrogel for drug or protein delivery. Incorporation and release of these molecules were evaluated in vitro as proof of concept for drug or protein encapsulation. Taken together, we expect that the hydrogels are excellent biocompatibility and low toxicity alone and as a block copolymer. In the meanwhile, the hydrogels have been demonstrated to support good cell viability, proliferation, and as a source for delivery of growth factors and drugs.

摘要.............................II
Abstract of the Dissertation....III
致謝.............................IV
Table of Contents................V
List of Figures..................X
List of Tables..................XVI
List of Schemes.................XVII
List of Abbreviations...........XVIII
CHAPTER I: General Introduction and Literature Review..........1
1    Environment Responsive Hydrogels..........7
2    Thermosensitive Polypeptide Hydrogels..........9
3    Gelation Mechanism of Hydrogel..........12
4    Biomedical Applications of Thermosensitive Hydrogels..........14
CHAPTER II: Oligo(alanine)-modified Methoxy- Poly (ethylene glycol) and Charged oligo(peptide) Material: Synthesis, Characterization, and Biological Properties..........18
1    Introduction..........19
2    Aim of This Study..........20
3    Experimental Section..........22
3.1    Materials..........22
3.2    Synthesis of mPEG-P(Ala), mPEG-P(Ala)-Lys, and mPEG-P(Ala)-Asp Block Copolymer and Analyzed by Gel Permeation Chromatography (GPC)..........23
3.3    1H Nuclear Magnetic Resonance (NMR) Spectroscopy..........25
3.4    Dynamic Light Scattering (DLS) and Zeta Potential..........25
3.5    Transmission Electron Microscopy (TEM)..........26
3.6    Circular Dichroism (CD) Spectroscopy..........26
3.7    Characterization of Micelles..........26
3.8    Fourier Transformed Infrared Spectroscopy (FT-IR)..........27
3.9    Solution-gel (sol-gel) Phase Transition..........27
3.10    Rheological Properties..........28
3.11    Scanning Electron Microscope (SEM)..........28
3.12    Biocompatibility Tests..........28
3.13    Degradation Test..........29
3.14    Drug Releasing Properties Tests..........29
4    Results and Discussion..........30
4.1    Synthesis of Block Copolymer..........30
4.2    Nano-assembly of mPEG-P(Ala), mPEG-P(Ala)-Lys, and mPEG-P(Ala)-Asp Block Copolymer..........34
4.3    The Functional Group and Secondary Structure of mPEG-P(Ala), mPEG-P(Ala)-Lys, and mPEG-P(Ala)-Asp Block Copolymer..........37
4.4    Gelation Properties..........41
4.5    Biocompatibility Tests..........43
4.6    In Vitro Biodegradability..........45
4.7    Release of BSA from mPEG-P(Ala) Hydrogels..........46
4.8    Release of BSA from Charged Polypeptide Hydrogels..........47
4.9    The Release Profile of Model Drug Doxorubicin Encapsulated in mPEG-P(Ala) Hydrogels..........48
4.10    The Release Profile of Model Drug Doxorubicin Encapsulated in Charged Polypeptide Hydrogels..........50
4.11    The Release Profile of Hydrophobic Drug Tacrolimus Encapsulated in Charged Polypeptide Hydrogels..........51
5    Brief Summary..........54
CHAPTER III: Oligo(alanine)-modified Methoxy- Poly (ethylene glycol) Hydrogels: Distinct Microarchitecture and Maintenance of Beta Cell Clusters..........56
1    Introduction..........57
2    Aim of This Study..........59
3    Experimental Section..........59
3.1    Biocompatibility Tests..........59
3.2    Recombinant Mouse Vascular Endothelial Growth Factor (rmVEGF) Controlled Release..........60
3.3    Culture of MIN6 Cells..........60
3.4    Glucose-Stimulated Insulin Secretion of Encapsulated MIN6 Cells..........61
3.5    Measurement of Insulin..........61
3.6    Immunostaining..........62
3.7    Animals..........62
3.8    MIN6 Cells Transplantations..........62
3.9  Immunostaining..........62
3.10  Statistics..........62
4    Results and Discussion..........63
4.1    Biocompatibility Tests..........63
4.2    The Distribution of the MIN6 Cell Clusters..........64
4.3    Release of VEGF from Hydrogel..........65
4.4    Glucose Stimulation Tests for the Encapsulated MIN6 Cells In Vitro..........66
4.5    In Vivo Subcutaneous Transplantation of MIN6 Cells Embedded in Hydrogels..........67
5    Brief Summary..........69
CHAPTER IV: Polypeptide-modified Thermosensitive Hydrogels: Adjustable Gelation Properties and Their Potential as a Drug Carrier..........70
1    Introduction..........71
2    Aim of This Study..........72
3    Experimental Section..........73
3.1    Synthesis of ʟ-alanine N-Carboxyanhydride (Ala-NCA), ʟ-lysine-(Z) N-Carboxyanhydride (Lys-(Z)-NCA), and P–Lys–Ala–PLX Block Copolymer..........73
3.2    1H Nuclear Magnetic Resonanc (NMR) Spectroscopy..........74
3.3    Fourier Transformed Infrared Spectroscopy (FT-IR)..........74
3.4    Scanning Electron Microscope (SEM)..........75
3.5    Degradation Test..........75
3.6    Biocompatibility Tests..........75
3.7    In Vitro Controlled Release of Tacrolimus (FK506)..........76
3.8    Drug Release In Vivo..........76
4    Results and Discussion..........77
4.1    The Synthesis and Characterization of P–Lys–Ala–PLX and Pluronic F-127..........77
4.2    Development of Mixed Hydrogel Formulation..........79
4.3    Biodegradability Test..........80
4.4    Biocompatibility Tests..........82
4.5    Tacrolimus Encapsulation and Release..........84
5    Brief Summary..........85
CHAPTER V: Conclusions..........87
1    The Biomedical Applications of Amphiphilic Block-copolymers..........88
2    In Situ Gelling-polypeptide Hydrogel Systems for the Subcutaneous Transplantation of MIN6 Cells..........89
3    A Mixed Hydrogel System for Sustained Delivery of Tacrolimus for Immunosuppressive Therapy..........90
REFERENCES..........93
APPENDIX..........103
1    Experimental Section..........104
2    Supplementary Results..........107
                                

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