光動力觸發微脂體化療藥物輸送系統之研究

Abstract

癌症為現代人類主要的死亡原因之一，目前常使用之治療方式中，將化療藥物包覆於微脂體之劑型，雖然能有效降低化療藥物副作用，但也減慢藥物釋放速度，使其療效大幅減弱。近年來我們發展利用光動力效應加速化療藥物由微脂體釋出之雙效微脂體，並發現其除了具有光動力治療與化學治療各自之效果外，還能造成微脂體中化療藥物釋放模式的改變，進而更加提高在活體動物實驗中對腫瘤之療效。為了驗證雙效微脂體的概念，並擴大其適用範圍，在本研究中，我們針對另一同因藥物釋放緩慢問題，而無法產生良好療效之微脂體藥物進行改良，建立結合光動力治療的雙效微脂體，並證實即使包覆不同化療藥物，依然能產生優良治療效力，對體積較大的腫瘤(500 mm3)也能發揮治癒功效。接著我們更進一步探討雙效微脂體的作用機制，發現其能藉由改善藥物釋放、增加藥物在腫瘤部位累積，以及促進藥物進入腫瘤細胞作用，來達到增進腫瘤治療能力的結果。最後我們更嘗試針對目前除手術外，並無較佳治療方式之人類惡性周邊神經鞘瘤進行治療探討。發現在小鼠腫瘤模式的實驗中，雙效微脂體能減少化療藥物的使用量，於治療後進行血液生化分析，顯示此治療方式具良好使用安全性，而且依然能展現完全清除腫瘤的功效，代表對人類惡性周邊神經鞘瘤也能達到應用。經由對雙效微脂體的了解，希望使其能有更進一步的發展，解決目前臨床腫瘤治療的需求。

Nowadays, cancer is one of the leading causes of mortality worldwide. Using liposome-encapsulated cancer chemotherapy significantly decreases side effects. However, entrapment of drug in liposomes may slow down drug release and attenuate anticancer efficacy. Previously, a dual-effect liposome triggered by photodynamic effect (PDT) was developed to improve the therapeutic efficacy of chemotherapeutic agent-loaded liposomes. Co-encapsulation of the photosensitizer and chemotherapeutic agent in liposome not only could display PDT and chemotherapy effect but also change the release profile of the chemotherapy drug from liposome, enhancing the anti-tumor effect in animal study. To verify the concept of dual-effect liposome and apply this strategy for cancer treatment, encapsulation of another liposomal chemotherapeutic agent in dual-effect liposome was performed. This newly dual-effect liposome could enhance anti-cancer efficacy even encapsulated with other chemotherapy drugs and revealed significant therapeutic effects even on large tumors (500 or 1000 mm3). Investigation of mechanism of dual-effect liposome showed that dual-effect liposome enhanced anti-cancer efficacy by (1) changing drug release, (2) increasing drug accumulation at the target tumor site, and (3) improving more chemotherapeutic medicine to enter the tumor cell. Treatment with dual-effect liposome significantly prevented tumor growth of malignant peripheral nerve sheath tumor (MPNST) which is a neurofibrosarcoma from neurofibromatosis type 1 and difficult to be cured. Analysis of blood chemistry showed it is safe to use dual-effect liposome for cancer treatment in murine model. In this study, we evaluated the feasibility of using dual-effect liposome to treat human cancer tumor xenografts in vivo, and expected to apply dual-effect liposome to clinical cancer therapy in the near future.