mPEG-PLGA溫度敏感型水膠製備及其不同共聚物組成對藥物輸送系統之影響研究

Thermosensitive mPEG-PLGA hydrogels：Synthesis and effect of copolymer composition on the drug delivery system

李郁旻(Yu-Min Lee)

指導教授 ： 朱一民

國立清華大學/工學院/化學工程學系/碩士(2010年)

摘要

本研究主要探討不同共聚物組成對兩性共聚物於藥物輸送系統
之影響。實驗利用開環聚合反應製備mPEG-PLGA兩團聯共聚物，其中[PLGA]/[mPEG]之比例由1.46至3.10，並分別以分子量350、550和750之methoxy poly(ethylene glycol)(mPEG)作為親水鏈段。結果顯示，除了mPEG350系列及[PLGA]/[mPEG]比例為3.10之共聚物不溶於水，其他兩團聯共聚物水溶液皆可形成奈米微胞，臨界微胞濃度低於1×10-2 mg/ml。mPEG550與mPEG750系列共聚物具有溫度敏感性，以mPEG-PLGA(550-1405)共聚物的成膠範圍最廣。此外，mPEG750系列共聚物成膠溫度較高，故不適用於人體體內。降解機制以mPEG與酯鍵鍵結處先被水解，接著為PLGA疏水鏈段降解，尤其以GA鍵結處(G-G, G-L)易先水解，較疏水的LA鍵結處(L-L)則較慢降解。細胞毒性及溶血試驗證實，此材料具有良好生物相容性。藥物釋放初期無突釋現象，能持續穩定釋放藥物Teicoplanin，以水膠濃度15wt% mPEG-PLGA(550-1405)為最適化藥物輸送系統，可釋放藥物達31天。藥物釋放前九天以水膠濃度15wt%之系統釋放最快，20wt%次之，25wt%最慢；九天後則以25wt%釋放最快，15wt%最慢，乃因水膠降解之寡聚物產生結晶行為所致。動物實驗結果顯示，此藥物輸送系統能有效治療患有骨髓炎的紐西蘭兔。本研究不僅探討不同組成對藥物輸送系統之影響，並證實此藥物輸送系統應用於局部抗生素釋放治療骨髓炎之可行性。

關鍵字

水膠 ； 溫度敏感性 ； 藥物輸送系統 ； 骨髓炎 ； 得時高

並列摘要

The purpose of this study is to understand the effect of copolymer composition on the drug delivery system. A series of biodegradable mPEG-PLGA diblock copolymers, [PLGA]/[mPEG] ratio from 1.46 to 3.01, were synthesized by ring-opening polymerization. Methoxy poly(ethylene glycol)(mPEG) of 350, 550 and 750, were used as the hydrophilic segment. Our results showed that copolymers of mPEG350 series and [PLGA]/[mPEG] at 3.01 were insoluble in water. The other copolymers in aqueous solution formed nanoparticles with critical micelle concentrations below 1×10-2 mg/ml. mPEG550 and mPEG750 series copolymers had thermosensitive properties with mPEG-PLGA(550-1405) having a wider gelation window. However, the gelation temperatures of mPEG750 series copolymers were above body temperature. Initially, hydrolysis occurred at the ester linkage of mPEG, which was followed by PLGA degradation occurring preferentially in GA unit rather than LA unit due to their hydrophobicity. Cytotoxicity and hemolysis test indicated that mPEG-PLGA diblock copolymers were biocompatible. Drug release study showed no initial burst and 15 wt% mPEG-PLGA(550-1405) hydrogel had the optimal drug release behavior. Before day9, drug release rate decreased as the concentration of copolymer aqueous solution increased. But this relationship inverted after day9. We inferred that this was due to the crystallization of degraded oligomer in the hydrogel. In vivo study showed that implantation of the mPEG-PLGA hydrogel containing Teicoplanin was effective in treating osteomyelitis in rabbits. The effect of copolymer composition on the drug delivery system was elucidated in this study. The use of mPEG-PLGA-based biodegradable hydrogels may hold great promise as a therapeutic strategy for osteomyelitis.

並列關鍵字

hydrogel ； thermosensitive ； drug delivery system ； osteomyelitis ； Teicoplanin

參考文獻

23 Sia, I. G. & Berbari, E. F. Osteomyelitis. Best Practice & Research in Clinical Rheumatology 20, 1065-1081 (2006).

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