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

Injectable thermosensitive polypeptide hydrogel mPEG-P(Ala)-P(Asp) :Gelation studies and application for drug delivery

鄭傑(Jheng, Jie)

指導教授 ： 朱一民

國立清華大學/工學院/化學工程學系/碩士(2016年)

摘要

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。

關鍵字

胺基酸水膠 ； 溫度敏感性 ； 藥物投遞

並列摘要

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.

並列關鍵字

polypeptide hydrogel ； thermosensitive ； drug delivery

參考文獻

[2] Gopferich, A.; Tesmar, J. Polyanhydride degradation and erosion. Advanced Drug Delivery Reviews. 2002, 54, 7, 911-931.

[3] Uhrich, K. E.; Cannizzaro, S. M.; Langer, R. S.; Shakesheff, K. M. Polymeric systems for controlled drug release. Chemical reviews. 1999, 99, 11, 3181-3198.

[4] Ward, M. A.; Georgiou, T. K. Thermoresponsive polymers for biomedical applications. Polymers, 2011, 3, 3, 1215-1242.

[6] Winzenburg, G.; Schmidt, C.; Fuchs, S.; Kissel, T. Biodegradable polymers and their potential use in parenteral veterinary drug delivery systems. Advanced drug delivery reviews, 2004, 56, 1453-1466.

[7] Jeong, B.; Bae, Y. H.; Lee, D. S.; Kim, S. W. Biodegradable block copolymers as injectable drug-delivery systems. Nature, 1997, 388(6645), 860-862.