利用脂質體傳輸二羥基順鉑−法尼基硫柳酸共軛抗癌藥物

Abstract

癌症相關議題長期困擾著人類，隨著人口的增長和衰老，問題變得更加嚴重。 順鉑(cisplatin)為常用的抗癌藥物之一，其主要的細胞毒活性是通過與DNA中的鳥嘌呤螯合而產生。但是順鉑同時具有低選擇性等多種副作用，因此其使用受到限制。過去研究有展現出許多降低毒性的前驅藥方法。非共價前驅藥是一個突出的例子，藉由將順鉑包封在脂質體中以提高選擇性，減少副作用並獲得所需的生物分佈。 組合療法(combination therapy)搭配脂質體傳輸是提高抗癌藥物效率的好方法。法尼基硫柳酸(salirasib)是Ras蛋白抑制劑，也是抗癌藥的候選藥物。然而無法精確控制脂質體包封兩種藥物的比例成為法尼基硫柳酸和順鉑組合療法所面臨的挑戰。為了解決藥物開發的比例問題，本篇論文展現了順鉑的Pt（IV）前驅藥二羥基順鉑(oxoplatin)經由可生物裂解的鍵結與法尼基硫柳酸形成共軛藥物，用於脂質體封裝。使用這種共價鍵鍵結方法可確保兩種抗癌藥的比例，並在特定的癌症環境中以兩種藥物的形式釋放，從而增強細胞毒性的功效。本論文不僅表徵了二羥基順鉑-法尼基硫柳酸脂質體的性質，而且揭示可能的藥物釋放機理。預期此二羥基順鉑-法尼基硫柳酸共軛藥物的脂質體可以選擇性標靶癌細胞，並且展現協同或加成的毒殺效果。

Cancer has troubled humans for a long time, and becomes even more problematic with increasing population and aging. Cisplatin is one of commonly used anticancer drugs to cause cytotoxicity mainly by chelation with guanines in DNA. The use of cisplatin is limited due to the side effects of its nonselective nature. There are several approaches of prodrugs to lower systemic toxicity. One prominent example of noncovalent prodrugs is to encapsulate cisplatin in liposomes to improve selectivity, reduce side effect and gain the desired biodistribution. Combination therapy along with liposomal delivery is a good approach to improve the efficiency of anticancer drugs. Salirasib is a Ras protein inhibitor and candidate of anticancer agent. Though combination of salirasib and cisplatin can be applied in therapy, the proportion of two drugs for liposomal encapsulation cannot be precisely controlled. To solve this problem in drug development, herein, we demonstrate that oxoplatin, a Pt(IV) prodrug of cisplatin, can conjugate with salirasib via a bio-cleavable linker for liposomal encapsulation. This covalent linkage method ensures the ratio of two anticancer agents, which will be released as two free drugs in the specific cancer environment to enhance the efficacy of therapy. In this study, not only the property of oxoplatin-salirasib liposome was characterized, but also the mechanism for releasing drugs was determined. The liposomal oxoplatin-salirasib conjugate is expected to selectively target cancer cell and exert synergistic or additive cytotoxicity.