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標題: γ- Glutamyl Transferase Activated Water Soluble Polymer-Adriamycin Conjugates
作者: Chang, Huang-Chuan
關鍵字: 抗癌藥物
anticancer drug
water-soluble polymer drug conjugates
γ-glutamyl transferase
enhanced permeability and retention effect
出版社: 化學工程學系
摘要: Targeting effect of anticancer compounds has receiving most attentions in development of effective drug delivery systems. The efficacy of anticancer agents is usually limited by its highly nonspecific cytotoxicity to normal cells. An effective water-soluble polymer drug conjugate is designed and proposed according to the anatomic conditions of cancer cells. The designed system is expected to mostly remain stable during circulation while an effective release of parent drug takes place upon the arrival of the prodrug at the tissues of cancer cells. In addition, the enhaced permeability and retention effect (EPR) of tumor cells will highly facilitate the accumulation space of water-soluble polymer drug conjugates in the vicinity of tumor, which, consequently, promote the rate of pinocytic uptake of this polymeric prodrug into the targeted cells. In this study, HPMA copolymers containing p-nitroanilide in the side chains were synthesized and their physicochemical properties characterized. The average molecular weights of the copolymers were determined by Fast Protein Liquid Chromatography using Supreose 12 as a column. The mole contents of p-nitroanilide were evaluated by UV/Vis spectrophotometer. The release rates of p-nitroaniline by γ-glutamyl transferase were dependent on the content of p-nitroaniline. With increasing the mole content of p-nitroanilide, the release rate was enhanced. However, the release of p-nitroaniline decreased as aggregation of the copolymers in aqueous solutions occurred. It clearly demonstrated that the design of the molecular structure of polymer-drug conjugate in this study is highly practical for the targeting of cancer cells.
抗癌藥物之標的功能研究一直為藥物傳遞系統之重要研究課題,其原因在於化學治療之抗癌藥物的高度非選擇性細胞毒性,本研究針對腫瘤細胞組織之特性,設計一水溶性抗癌藥物複合體,此高分子前驅藥物將於血液循環中保持穩定性,使其藥物之細胞毒性對正常細胞傷害減低至最低程度。利用特殊化學結構,待高分子藥物到達癌細胞附近時,能夠有效的釋放出來,並利用癌細胞本身特殊的增強滲透與貯留效果之作用,來增加癌細胞對水溶性高分子藥物的細胞攝食,以增強水溶性高分子藥物標的功能。而在此研究中,分別合成HPMA單體一及穀胺酸轉化酵素可水解之單體二,並進行共聚合反應。其物化性質亦一併於本計畫中探討,而共聚合高分子平均分子量由FPLC測定,高分子支鏈上的p-nitroanilide莫耳含量也由紫外光/可見光光譜儀測定。並測定高分子接受酵素分解將p-nitroanilide釋放出來的情形,實驗結果發現穀胺酸轉化酵素γ-glutamyl transferase可催化此藥物模型的釋放。且當此p-nitroanilide的莫耳含量適度增加時,釋放之速率亦隨之增加,但當其含量過高時,則造成高分子支鏈的疏水性增加,導致高分子於水相中的聚集,反而會造成了其釋放速率的大幅降低。故本研究中證實此水溶性高分子藥物設計係唯一可行之抗癌標的方式。
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