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研究生:鄭傑
研究生(外文):Jheng, Jie
論文名稱:mPEG-P(Ala)-P(Asp)可注射溫度敏感型胺基酸水膠性質探討及其於藥物投遞上的應用
論文名稱(外文):Injectable thermosensitive polypeptide hydrogel mPEG-P(Ala)-P(Asp) :Gelation studies and application for drug delivery
指導教授:朱一民朱一民引用關係
指導教授(外文):Chu, I-Ming
學位類別:碩士
校院名稱:國立清華大學
系所名稱:化學工程學系
學門:工程學門
學類:化學工程學類
論文種類:學術論文
論文出版年:2016
畢業學年度:104
語文別:中文
論文頁數:61
中文關鍵詞:胺基酸水膠溫度敏感性藥物投遞
外文關鍵詞:polypeptide hydrogelthermosensitivedrug delivery
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本研究探討可注射溫度敏感性胺基酸水膠成膠性質以及應用於藥物投遞上的潛力。甲氧基化聚乙二醇-聚左旋丙胺酸(methoxy-poly(ethylene glycol)-poly(L-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-alanine(NCA-alanine)開環聚合反應合成;再以N-carboxyl anhydride β-benzyl L-Aspartate開環聚合並去除保護基,再末端接上天門冬胺酸,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(L-alanine), mPEG-P(Ala) -P(Asp)水膠。
實驗結果顯示聚胺基酸高分子水溶液可以形成微胞,臨界微胞濃度約為0.65-0.11 wt% ; 微胞表面電位及粒徑量測顯示,隨著聚合上mPEG-P(Ala)的左旋天門冬胺酸莫耳數不同,其表面電位由20 mV降低至-20 mV,粒徑大小約為100-250 nm;TEM及表面電位觀測顯示微胞表面電位影響微胞的形貌;SEM觀測水膠能夠形成三維網狀結構;由流變儀觀察胺基酸水膠的黏度及機械性質隨著溫度而變化顯示具有溫度敏感性;MTT assay 顯示水膠具有良好的生物相容性;水膠降解實驗顯示胺基酸水膠需透過酵素進行降解;水膠包覆抗癌藥物順鉑的結果顯示藥物的釋放可由接上不同莫耳數的天門冬胺酸比例控制,達到持續的藥物釋放。
由以上實驗結果顯示,mPEG-P(Ala) -P(Asp)胺基酸水膠為一良好的藥物控制釋放載體,具有原位成膠、良好的生物相容性、降解性等特性,對於局部的藥物治療應用上具有相當的優勢。

The Objective of this study was to discuss the thermoresponsive polypeptide hydrogel properties and the potential of hydrogel in drug delivery. methoxy-poly(ethylene glycol)-poly(L-alanine) (mPEG-P(Ala)) is a well-known thermoresponsive polypeptide hydrogel. By using mPEG-NH2 and N-carboxy anhydride-alanine (NCA-alanine) through ring-opening polymerization. Afterwards, using N-carboxyl anhydride β-benzyl L-Aspartate through ring-opening polymerization and removal of the benzyl protecting groups to form the hydrogel.

The experimental results indicated that the polypeptide polymer with hydrophilic and hydrophobic parts can form a micelle structure in water. The critical micelle concentration (CMC) was ranged from 0.65 to 0.11 wt%. Zeta potential and particle size measurements of micelle indicated that the number of different mole L-aspartic acid were conjugated to mPEG-P(Ala), the Zeta potential decreased from 20 mV to -20 mV and particle size is about 100-250 nm. TEM and Zeta potential observations indicated that the morphology of micelle affected by Zeta potential. SEM results showed that hydrogel can form three-dimensional network structure. Rheology results showed that viscoelastic properties of the polypeptide hydrogel varied with temperature, indicative of the formation of a gel.
MTT assay studies suggested acceptable biocompatibility of the hydrogel and the degradation of hydrogel was accelerated in presence of enzyme.
The results of cisplatin encapsulated in hydrogel indicated that the continuous drug release can be controlled by the number of different mole L-aspartic acid were conjugated.
From the above results, mPEG-P(Ala) -P(Asp) is a good drug controlled release carriers. It has In-Situ gelling, biocompatibility and biodegradability properties. For the local application of drugs has a considerable advantage.

目錄

摘要 I
Abstract III
第一章 文獻回顧 1
1.1生物可降解高分子簡介 1
1.2藥物控制釋放系統 4
1.3 藥物控制釋放機制 5
1.4 高分子降解機制 6
1.5 高分子降解類型 7
1.6 高分子水膠 8
1.6.1水膠簡介 8
1.6.2 聚酯類溫度敏感型水膠 9
1.6.3 聚胺基酸類溫度敏感型水膠 12
1.7 親水性抗癌藥物順鉑(Cisplatin, cis-diamminedichloroplatinum (II),CDDP)及其藥物作用機制 16
第二章 研究動機與目的 19
第三章 實驗方法 21
3.1實驗藥品 21
3.2實驗儀器與裝置 22
3.3實驗架構 23
3.4水膠合成步驟 24
3.4.1合成mPEG-NH2 24
3.4.2 N-carboxyl anhydride of L-Alnine (NCA-Alanine)環化反應 24
3.4.3 mPEG-P(Ala)開環聚合反應 25
3.4.4 N-carboxyl anhydride of β-benzyl L-Aspartate (NCA-Asp(Bzyl))環化反應 25
3.4.5 mPEG-P(Ala)-P(Asp(Bzyl))開環聚合反應 25
3.4.6 mPEG-P(Ala)-P(Asp(Bzyl))去保護基反應 26
3.5實驗方法 27
3.5.1核磁共振光譜鑑定(1H-NMR) 27
3.5.2全反射傅立葉轉換紅外光譜儀(ATR-FTIR) 27
3.5.3水膠相轉變測定(Test tube inverting method) 27
3.5.4流變儀(Rheology) 28
3.5.5穿透式電子顯微鏡(Transmission electron microscope,TEM) 28
3.5.6掃描式電子顯微鏡(Scanning electron microscope,SEM) 29
3.5.7臨界微胞濃度(CMC) 29
3.5.8動態光散射及介面電位量測儀(DLS &Zeta potential) 30
3.5.9水膠體外降解測試 30
3.5.9水膠包覆順鉑體外藥物釋放 31
3.5.10 水膠體外毒性檢測 MTT assay 31
第四章 實驗結果與討論 33
4.1 mPEG-P(Ala)-P(Asp)嵌段共聚物結構鑑定 33
4.1.1核磁共振光譜鑑定(1H-NMR) 33
4.1.2 傅立葉轉換紅外光譜官能基鑑定(FTIR) 36
4.2水膠相轉變測定(Test tube inverting method) 37
4.3水膠全反射傅立葉轉換紅外光譜分析(ATR-FTIR) 38
4.4水膠微胞性質及型態觀察 42
4.5水膠材料表面結構測定(SEM) 47
4.6水膠流變性質分析(Rheology) 48
4.7水膠體外降解測試 51
4.8水膠包覆順鉑體外降解藥物釋放 52
4.9水膠體外毒性檢測 MTT assay 55
第五章 結論與未來展望 56
第六章 參考文獻 58
附錄 61

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