開發用於遞送缺氧選擇性藥物之奈米脂質載體

Abstract

Hypoxia-activated Prodrug X (HAPX) 是一種被發展做為治療具有抗藥性腫瘤的藥物。然而，它在臨床使用上有幾個障礙，包含體內半衰期短、低溶解度、低腫瘤累積量以及低患者依從性等特性。這項研究的目的是建立脂質載體 (lipid-based carriers) 來包覆HAPX以解決上述問題。脂質載體的製備方式，採用了低溫乳化法 (cold emulsification method) 搭配inverse micelleformation以提升HAPX的包覆率，並以HPLC來分析HAPX在經過劑型製備以及長期儲存後是否會發生降解的情形以及脂質載體的穩定性。雖然細胞實驗顯示以脂質載體包覆HAPX後，對C26細胞的毒性雖然與未包覆的HAPX相當，但體內組織分佈研究卻發現，HAPX經過脂質載體包覆後，其在腫瘤部位比起未包覆的HAPX有更顯著的累積量，而且顯著提升了腫瘤的抑制能力和降低了HAPX的副作用。

Hypoxia-activated prodrugX (HAPX) has been developed for the treatment of chemotherapy-resistant tumor. Several obstacles of HAPX have been found in the clinical use, such as short half-life in bodies, unfavorable physical characteristics of low solubility, low partition coefficient and low patient compliance. The purpose of this study was to overcome these obstacles by developing a lipid-based carrier to deliver HAPX. The adopted strategy utilizes inverse micelle formation and the cold emulsification method to enhance the entrapment efficiency of HAPX. Drug degradation and long-term storage stability of HAPX in this lipid-based carriers were performed through HPLC analysis. To evaluate the therapeutic efficacy, in vitro and in vivo studies were conducted. Although the in vitro studies showed that HAPX in lipid-based carriers possessed insignificant cytotoxic effects on C26 cells, the in vivo tissue distribution studies demonstrated that the accumulation of HAPX in lipid-based carriers is significantly higher than that of free-form HAPX in tumor site. The in vivo therapeutic efficacy was conducted in C26 tumor-bearing mice. Mice treated with lipid-based carriers containing HAP showed greater tumor suppression ability than the mice group which received free-from HAPX.