以聚胺基酸水膠mPEG-p(Ala)-p(Lys)作為口服藥物奧曲肽投遞系統之應用

Drug Delivery System for Oral Octreotide Based On Polypeptide Hydrogel mPEG-p(Ala)-p(Lys)

陳怡蓁(Yi-Chen Chen)

指導教授 ： 朱一民

國立清華大學/工學院/化學工程學系/碩士(2021年)

摘要

本研究以一具有 pH 敏感及溫度敏感特性之聚胺基酸水膠 mPEG-p(Ala)-p(Lys)(methoxy-poly(ethylene glycol)-poly(L-alanine)-poly(L-lysine)) 作為口服藥物奧曲肽載體，探討其成膠性質及其在藥物投遞應用上之潛力。將 methoxy-poly(ethylene glycol)(mPEG)末端的-OH 改質為-NH2 後與 NCA-alanine 進 行開環聚合形成 mPEG-p(Ala)，接著與不同比例之 L-lysine(Z)進行第二次開環聚 合，並切除保護基，形成具 pH 敏感特性的 mPEG-p(Ala)-p(Lys)，欲探討不同長 度的 p(Lys)鏈段對藥物釋放的效果差異。
此材料經由 NMR、GPC 及 FTIR 鑑定證實合成成功，其高分子水溶液可形成 微胞，臨界微胞濃度介於 0.03~0.068 wt%，微胞粒徑大小約為 60~90 nm。以倒置 法測試材料之成膠性質，結果顯示依不同 p(Lys)鏈段長度，約在 14~15 wt%可在 20~25°C下成膠。材料表面結構呈現三維網狀結構，具有足夠大小與空間提供藥 物包覆及水份通透性。Zeta potential 結果顯示隨環境 pH 值下降，p(Lys)質子化程 度較高因此有較高的表面電位。水膠含水率及膨潤率則隨 p(Lys)鏈段長度的增加 及環境 pH 值的下降而增加。水膠降解測試則表明具較長 p(Lys)鏈段之水膠較易 降解產生重量損失，進而影響藥物釋放結果。此材料包覆奧曲肽之包覆率可達 97% 以上，可將投入之藥物完整包覆在水膠材料當中。體外釋放結果顯示 L10 因降解 快速可在兩天內釋放 98%的藥物總量，較 L2 的 74%來得多，但其在體外生物毒 性測試有較低的生物相容性，因此在應用上 L2 水膠會是較佳的選擇。綜合以上 結果表明 mPAL 水膠材料在作為口服藥物載體應用及藥物控釋上具一定潛力。

關鍵字

水膠 ； 藥物載體 ； pH/溫度敏感 ； 聚離胺酸 ； 奧曲肽

並列摘要

In this study, a pH/thermo-sensitive polypeptide hydrogel methoxy-poly(ethylene glycol)-poly(L-alanine)-poly(L-lysine)(mPEG-p(Ala)-p(Lys)) with different length of poly(L-lysine) was synthesized and used as a drug carrier of the octapeptide drug, octreotide. The -OH group on methoxy-poly(ethylene glycol)(mPEG) was first modified to -NH2, and NCA-Ala was co-polymerized with mPEG at the N-terminal end by ring-opening polymerization to form mPEG-p(Ala). Afterwards, mPEG-p(Ala) was co-polymerized with NCA-Lysine and the protecting groups were removed to form mPEG-p(Ala)-p(Lys). The effect of different p(Lys) segments on drug release behavior was investigated.
The structure and molecular weight of the polymer were analyzed by NMR, FTIR and GPC. The polymer with different length of p(Lys), L2 and L10, could form gel at a concentration of 14~15 wt% at 22~24°C. The three-dimensional network structure of the hydrogel was observed by SEM, providing drug encapsulation space and water permeability. The zeta potential of mPAL increased as the pH decreased due to different protonation degree of the p(Lys) segment. The water content and swelling ratio were higher when the p(Lys) segment was longer and the pH value was lower. Hydrogel with longer p(Lys) segment also had higher degradation rate, influencing the drug release properties. The drug encapsulation efficiency could approach 97~99% for both L2 and L10. The results of in vitro release showed that L10 could release most of the encapsulated octreotide in 2 days due to its fast degradation, but L2 could only release 74%. Though L10 had better controlled release behavior in gastrointestinal digestive system but it had lower cell compatibility than L2. Thus, L2 might be a better choice for delivering oral Octreotide. Based on aforehand results, mPAL hydrogel shown to have a good potential in oral drug delivery and controlled release.

並列關鍵字

Hydrogel ； Drug delivery system ； pH/thermo-sensitive ； Poly(L-lysine) ； Octreotide

參考文獻

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