發展 Irinotecan 與 Chlorin e6 雙效微脂體藥物

Abstract

癌症為造成人口死亡的重要原因，多年來一直高居世界人口的十大死因第二名，而隨著醫療發展的進步與新藥的開發，針對不同癌症，病患獲得更好的治療，癌症的預後結果也隨之改善。然而，在癌症治療過程中，癌細胞對治療產生抗性的而造成治癒效果不佳一直是治療上所需面對的問題。對於治療這些具有抗藥性的癌症，目前有效的方式之一為併用療法: 透過併用兩種或以上不同毒殺機制的藥物治療癌症。本篇研究即希望透過併用藥物以及微脂體劑型，製備出雙效微脂體作為一併用療法。本研究的第一部分，我們將化療藥物 Irinotecan (IRT) 以及光感物質 Chlorin e6 (Ce6) 同時包覆在微脂體中，希望藉由化療藥物與光動力治療的搭配毒殺表現ABCG2的抗性細胞。在此一部分，我們利用細胞實驗來驗證此一微脂體對細胞的毒性以及探討可能的毒殺機制。此外，我們利用添加同銅離子以及改良雙效微脂體的製備方法，針對此一微脂體的在血漿中的穩定性做進一步的優化。第二部分，我們希望利用化療藥物 IRT 搭配天然植物萃取物 Curcumin (CUR) 發展出另一種併用療法，用於治療因化學藥物誘發表現 COX-2 基因的癌細胞。這一部分的研究主要探討微脂體 IRT與 CUR兩種藥物併用下毒殺細胞的效果，並進一步探討兩種藥物併用下對細胞 COX-2 基因表現量之影響。

For many years, cancer has been the leading cause of death in the world. Although the medical advances have improved the prognosis and treatments, the rate of recurrence and death for several types of cancer remain disappointingly high, and this is often due to drug resistance of the cancer. One of the more effective ways to treat drug-resistant cancers is combinational therapy: using two or more medications that exert different cytotoxic mechanisms. In this study, we sought to develop a combination therapy based on liposomal irinotecan (IRT) in combination with chlorin e6 (Ce6) or curcumin (CUR). In the first part of our study, IRT and Ce6 were coloaded into PL-IRT-Ce6 liposomes. The liposome was developed to kill drug-resistant cancer cells that express the drug efflux transporter ABCG2. The cytotoxicity and the possible cytotoxic mechanism of PL-IRT-Ce6 were examined by in vitro studies. In addition, we improved the stability of PL-IRT-Ce6 by adding Cu2+ as the trapping agent of IRT as well as changing the liposome preparation method. In the second part of this study, we developed another combination therapy based on the use of liposomal IRT in combination with CUR, as CUR is thought to be able to downregulate IRT-induced expression of COX-2. In this latter part of the study, we focused on the cytotoxicity and the regulation of COX-2 expression when cells were treated with PL-IRT plus CUR.