Poly(ester)–graft–Poly(γ–glutamic acid) 兩性高分子之製備及其做為癌症藥物載體之應用

Preparation of the amphiphilic Poly(ester) graft–Poly(γ–glutamic acid) copolymer and its application as an anticancer drug carrier

張國勇(Kuo-Yung Chang)

指導教授 ： 李育德

國立清華大學/工學院/化學工程學系/博士(2009年)

摘要

結腸直膀癌是目前台灣地區主要癌症死亡原因的第三位，在全世界則是第二位。以化學療法對抗腫瘤所面臨的最大缺點在於藥物本身除了可殺死腫瘤細胞外，對其它器官及組織亦具有相當的危害性，造成正常組織的死亡。因此，就算痊愈但器官也產生不能負荷的傷害。此外，化學治療常常會發生癌細胞經自身的抵抗或基因突變，產生對癌症藥物的抗藥性，進而失去藥效，使癌症繼續蔓延而縮短病患的生命。本研究的核心技術是以抗癌藥物做為起始劑的新穎高分子聚合方法，開發出可攜帶兩種癌症藥物的奈米微胞載體，進而克服癌症藥物之高副作用及癌細胞之抗藥性的兩大障礙，其更有效地殺死癌細胞，提升治療效果。

本研究直接使用抗癌藥物(5’DFUR)為起始劑，單體(ε-caprolactone)或(lactide/glycolide) 經開環合成含藥物的5’DFUR-poly(ε-caprolactone) (5’DFUR-PCL)或5’DFUR-poly(lactide-co-glycolide)(5’DFUR-PLGA)高分子，再利用交聯的方法接枝於Poly (glutamic acid) (γ-PGA)，各自形成具有抗癌藥物的5’DFUR-PCL-γ-PGA及5’DFUR-PLGA-γ-PGA兩性高分子。而後使用紅外線光譜儀、核磁共振儀及膠體過濾層析儀對其結構做詳細鑑定。而後兩性高分子是以自我組裝的方式將第二種抗癌藥物包覆於微胞中，形成攜帶兩種抗癌藥物奈米粒子，並評估其藥物釋放的效率及於體外做為治療結腸直腸癌的效果。我們期盼本研究創新的聚合方法，可突破現有的合成技術，減少製程步驟並降低生產成本；另一方面，以雞尾酒療法概念所設計的奈米微胞載體，可有效地治療結腸直膀癌。

關鍵字

聚麩胺酸 ； 聚乳酸/聚甘醇酸共聚物 ； 兩性高分子 ； 藥物釋放

並列摘要

The colorectal cancer is the third death reason of the cancer in Taiwan, and the second in the world. The greatest defects of the anticancer drug for chemotherapy are able to kill normal cells but also cause the damage of the normal tissues or organs at the same time. Furthermore, the cancer cells can resist anticancer drug by themselves or through gene mutation by chemotherapy, resulting in forming drug resistances and losing the effect of the drugs. The main goal of this research is to develop a novel method of polymerization using an anticancer drug as the initiator, which produces nano-scale micelles with two kinds of anticancer medicines to overcome above defects. These micelles will kill cancel cells effectively and improve healing efficiency.

First, an anticancer drug (5’DFUR) is utilized directly to be an initiator in the polymerization, and ε-caprolactone or (lactide/glycolide) is polymerized to form the 5’DFUR-poly(ε-caprolactone) (5’DFUR-PCL) or 5’DFUR-poly (lactide-co-glycolide)(5’DFUR-PLGA) in this study. The 5’DFUR-PCL and 5’DFUR-PLGA are then grafted to Poly (glutamic acid) (γ-PGA) to form a comb-like amphiphilic copolymers respectively (5’DFUR-PCL-γ-PGA and 5’DFUR-PLGA-γ-PGA). The characteristics of the copolymers will be examined by FT-IR, NMR and GPC. Additionally, a second anticancer drug is coated on micelles of amphiphilic copolymers by self-assembly method in aqueous phase to from a micelle with two kinds of the anticancer medicines. The effects of drug delivery and cure of colorectal cancer in vitro will be investigated.

We expect that this novel polymerization method is able to replace the present technique, which would decrease the steps of the preparation process and reduce the prime cost; on the other hand, the nano-micelles carriers are designed from the concept of the cocktail therapy, might provide a way to cure effectively the colorectal cancer.

並列關鍵字

Poly(γ–glutamic acid) ； poly[lactide-co-glycolide], PLGA ； amphiphilic copolymer ； drug delivery

參考文獻

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