可調控式氫鍵作用力之超分子微胞材料應用於藥物控制釋放系統

Abstract

近年來以高分子為載體應用於藥物釋放之研究備受重視，本研究開發一簡單的合成路徑，製備出可大量化生產的超分子寡聚體微胞材料，以溫度刺激回應性的高分子聚丙二醇(Polypropylene glycol)為主體，在主鏈末端導入不同的胞嘧啶(Cytosine)衍生物，藉由多點式互補氫鍵的誘導下，促進微胞的形成。由於微胞穩定度在藥物傳遞的過程中是十分重要，故本研究將材料進行穩定度測試，(amine-cy)2PPG及(amide-cy)2PPG微胞材料皆擁有良好之穩定度，尤其是(amine-cy)2PPG無論是在臨界微胞濃度、分散劑之加入或是濃度的變化下皆表現出非常好的穩定度。另外，微胞材料在包覆藥物後，展現出可調的藥物負載量特性，並具有極高度的藥物負載率(>26%)，在高於微胞材料之最低臨界溶解溫度時，結構上會產生相轉變，進而將內部藥物釋出。另外，本研究開發之材料在包覆螢光性質的染料後也展現出絕佳的特性及包覆效益，未來發展潛力將可與以期待。細胞存活檢測(MTT)確認微胞材料具備良好的生物相容性，並在體外癌細胞毒殺實驗中，顯示出微胞材料具有非常好之溫度靈敏性和控制性，抗癌藥物在經過載體的包覆後可在更低的濃度下達到毒殺細胞的效果，是一具有重大突破且新穎之藥物傳遞材料。

Novel supramolecular micelles with stimuli-responsive abilities were successfully prepared through the complementary multiple hydrogen bonds and then applied for drug delivery systems. In this thesis, we designed a simple pathway and successfully achieved large-scale production of cytosine-end-capped polypropylene glycol derivatives from commercial sources. These new micelless are able to self-assemble through self-complementary hydrogen bonding interactions into a higher-level structure that can be easily fabricated into micelles in aqueous solution. The resulting micelles are very attractive from a practical point of view, since they have a very low critical micellization concentration (< 10-6 g/L) with very high loading capacity (> 26%), which makes them extremely stable and efficient loading process. Furthermore, we have also demonstrated a silimar approach for the use of Rhodomine dyes as chromophores in aqueous media through appropriate manipulation of supramolecular micelles, leading to a dramatic increase in real quantum yield of the dye while ensuring high loading efficiency of Rhodomine dye. In addition, MTT assay results confirmed an excellent in vitro biocompatibility of these micelless as well as Pluronic®. Release studies in vitro have shown that the antitumor activity of the released doxorubicin (Dox) is assessed using different cell lines. Dox-loaded micelles have the dose-dependent cytotoxicity to kill cancer cells at the body temperature. More importantly, the IC50 of DOX in micelles against drug resistant cells was significantly lower than that of free DOX after 24h of incubation. Thus, this newly developed approach provides a significant contribution to the development of next-generation drug deliver vehicle based on self-assembling supramolecular micelles as promising alternatives to existing systems, elaborate design in the supramolecular strategy.