sn-2石胆酸磷脂脂质体的构建及其性能研究

Developing liposome formulations with an active tumor specific drug release mechanism is a very attractive topic that has aroused much interest in drug delivery field for years. In design of liposome drug delivery systems, in order to prevent early-leak of drug-load from liposomes before they reach target sites, high transition temperature (long saturated acyl-chains) phospholipids and high content of cholesterols have been used to fabricate liposomes. These lipid compositions form a thick, tightly-packing lipid bilayer walls which ensure stable encapsulation of drug molecules in the liposome core. However, once liposomal drug carriers deposit to tumor tissues, these thick, compact lipid membranes become a hurdle for drug release from liposomes to exert their therapeutic effects thus efficacies of drug molecules compromise or even disappear. In this project, we will design novel sn-2 lithocholic acid or its derivative-conjugated phospholipids that are sensitive to secretory phospholipase A2 (sPLA2) which are found over-expressed at tumor sites. It is well-known that combination of bile acids and lipases including phospholipase A2 is the most effective way to digest lipid contents in nature. We hypothesized that the elevated level of sPLA2 selectively degrades sn-2 lithocholic acid-conjugated phospholipids in liposomes into lithocholic acid and their relevant lysophospholipids. Lithocholic acid released from sPLA2-mediated degradation consequently will enhance the activity of sPLA2 and help emulsify the lipid membrane. Synergistic action of lithocholic acid and sPLA2 expedite disintegration of the lipid membrane and facilitates release of encapsulated drug molecules from liposomes. Furthermore studies have showed that lithocholic acids induce apoptosis to a variety of tumor cells without hurt normal cells thus release of them at tumor sites aids to kill/inhibit tumor cells. The overall effect is enhancement of efficacy of the liposome formulation. This project will push the ideas that utilize tumor microenvironment to facilitate drug release from liposomes to a new level and may create a successful platform to develop FDA approved new drugs in the future.

脂质体在肿瘤部位的定点药物释放一直是研究热点之一，目前脂质体使用具高相变温度的长链饱和磷脂和高含量的胆固醇来构建磷脂膜，可稳定地将药物包裹在脂质体内核防止药物提前泄露，但到达肿瘤部位后，此稳定的磷脂膜同样阻止药物的释放，可导致疗效的降低甚至消失。本项目将采用前药原理以及利用引入敏感基团等方法设计出能被肿瘤部位高表达分泌型磷脂酶A2优先降解的sn-2位带石胆酸或其衍生物的新型嵌合磷脂并用于构建脂质体，已知胆酸和脂肪酶包括磷脂酶A2共同作用是自然界消化脂质最有效的形式，嵌合磷脂上石胆酸一旦被降解出来可以增强磷脂酶的活性同时自身也可乳化脂质体的磷脂层，配合磷脂酶必将导致脂质体在肿瘤部位的加速崩解以及被包裹药物的加速释放，同时研究表明石胆酸可选择性引起肿瘤细胞凋亡而不损伤正常细胞，此两者结合将提高配方的整体疗效，此研究将利用肿瘤微环境促进脂质体药物释放的研究推上新的高度，并有可能开发出国际一类新药