超分子微胞: 新世代材料在藥物釋放的應用

Abstract

高分子微胞為現今極具潛力之藥物傳遞材料，本研究中以最新思維修飾並增進微胞功能。在此將多點式氫鍵導入單聚高分子內，形成極具潛力之超分子藥物傳遞系統。此新穎之單聚高分子因氫鍵作用力誘發物理交聯，使之在水溶液下能自組裝形成微胞材料。此微胞擁有極低之臨界微胞濃度(CMC)，展現絕佳穩定度，且可降低表面作用力。此外，其擁有良好之生物相容性，在MTT測試下，對於人類腎胚胎細胞HEK-293，不具任何毒性。除此之外，在實際抗癌藥物Doxorubicin測試下，此材料能有效調控藥物負載量，且有效鎖住藥物，無任何遺漏釋放現象，具備高度控制性，在EPR系統理論下具備高度潛力。在細胞實驗中，包覆抗癌藥物Dox的微胞能有效毒殺人類肝癌細胞HepG2，令人震驚的，包覆藥物之微胞能經過吞噬作用(Endocytosis)進入癌細胞，準確的傳遞藥物並攻擊目標癌細胞，且不會破壞周圍組織，達到最佳療效。因此，本研究開發出新穎微胞材料，在藥物傳遞模擬系統具備極佳效果，在人類複雜生理中，為現今最具潛力之藥物傳遞材料。

A new concept to modify and enhance properties of existed functional micelles through self-complementary interaction has been exploited. In this thesis, a practical approach to the living polymerization of functionalized acrylic monomer allows for incorporation of self-constituted multiple hydrogen bonded groups into homopolymers with a potential application of supramolecular drug-delivery systems. These new homopolymers are able to self-assemble through multiple hydrogen bonding interactions into physically crosslinked structure that can be easily fabricated into micelles in aqueous solution. The resulting micelles have a very low critical micellization concentration, which makes them extremely stable and efficient at reducing surface tension. In addition, they possess excellent biocompatibility against the HEK-293 cell line (human erythrocyte kidney cell) by MTT assay. Moreover, we also observed that the incorporation of anticancer drug doxorubicin (DOX) affected the micellization process of micelles in aqueous solution and enabled the tuning of drug loading and release, being a powerful tool to adapt the EPR (Ehanced permeability and retention) system to specific requirements. Antitumor activity of the released Dox is assessed using the HepG2 human hepatocellular carcinoma cell line. Dox-loaded micelles have the dose-dependent cytotoxicity to kill cancer cells at the body temperature. Importantly, Dox-loaded micelles can be efficiently endocytosed by cancer cells, which allows them to serve as suitable vehicles of anticancer drugs for delivering effective, tumor targeting and metastatic disease. This newly developed material may provide a potential route towards next-generation drug deliver vehicles.