“#26029;臂式”#21452;重靶向肿瘤新生血管内皮细胞给药系统的构建及入胞机制研究

项目名称： “#26029;臂式”#21452;重靶向肿瘤新生血管内皮细胞给药系统的构建及入胞机制研究

项目编号： No.30873166

项目类型： 面上项目

立项/批准年度： 2009

项目学科： 无线电电子学、电信技术

项目作者： 何勤

作者单位： 四川大学

项目金额： 32万元

中文摘要： 脂质体表面的PEG化被广泛用于延长脂质体的循环时间从而通过EPR效应(增强的穿透和滞留效应)增加其在肿瘤组织的蓄积，实现向肿瘤组织靶向传递药物。然而PEG并非在肿瘤靶向的整个过程中都是有利的，当脂质体在肿瘤组织蓄积以后，PEG会防碍脂质体与肿瘤细胞的相互作用，抑制脂质体被肿瘤细胞摄取。在本研究中，具有还原敏感性的可断裂PEG被用于克服这一困境。在脂质体到达肿瘤组织以前，可断裂PEG存在于脂质体表面，这有利于脂质体充分利用EPR效应被动蓄积在肿瘤组织；到达肿瘤组织以后，该PEG链可以通过外源性地给予半胱氨酸（Cys）而脱离脂质体表面，PEG的位阻消失。为了进一步增加脂质体的入胞能力，"功能性分子"-细胞穿膜肽TAT被连接于较短的PEG链的末端，在循环的过程中TAT可以被长链的可断裂PEG屏蔽，在到达肿瘤组织以后，长链的可断裂PEG被移除，"功能性分子"-TAT被暴露出来从而介导脂质体高效地进入肿瘤细胞和血管内皮细胞。

中文关键词： 脂质体；可断裂PEG；TAT；EPR效应；靶向传递

英文摘要： Recently, PEGylation of liposome has been extensively employed to increase the circulation time of liposomes and enhance their accumulation in tumor tissue via EPR effect (enhanced permeation and retention effect). However, PEG is not always favorable in the whole process of tumor targeting: after the liposomes accumulate in tumor tissue, PEG may hinder the direct interaction between liposomes and cells and inhibit the uptake of liposomes. In this study, reduction-sensitive cleavable PEG modified liposomes were used to solve this dilemma. Before arrival at the tumor tissue,cleavable PEG presents on the surface of liposomes, which is useful for passive accumulation in tumor tissue; upon reaching the tumor tissues, the PEG chain could be removed by a safe cleaving reagent Cysteine (Cys), thus the steric hindrance of PEG could be overcome conveniently. To further improve the uptake of liposomes, a"functional molecule"-cell penetrating peptide TAT was attached to the distal end of a shorter PEG spacer anchored to the surface of liposomes, which could be shielded by longer cleavable PEG during circulation, upon arriving at tumor tissue, PEG was removed, thus the "functional molecule"-TAT was exposed and then liposomes could enter tumor cells and endothelial cells efficiently with the help of TAT.

英文关键词： liposome; cleavable PEG; TAT; EPR effect; targeted delivery