自组装型紫杉醇键合物前药的合成与性能

Synthesis and Properties of Self-assembling Paclitaxel Prodrug

以p-氨基苯乙酸(APA)和六亚甲基二异氰酸酯(HDI)为连接基团,将短链聚乙二醇单甲醚(mPEG)键合到紫杉醇(PTX)上,获得双亲型PTX前药mPEG-APA-PTX和mPEG-HDI-PTX。考察了这两种前药在自主装、体外药物释放动力学、体外细胞毒性和体内血浆清除速率等方面的表现。结果表明:两前药均能在水中自组装形成稳定的纳米颗粒,载药量高达28%;mPEG-HDI-PTX纳米颗粒在水溶液中非常稳定,细胞毒性很弱,在血液系统中清除很快,而mPEG-APA-PTX纳米颗粒在pH=7.4的环境下可缓慢释放出原药PTX,细胞毒性与临床用紫杉醇针剂Tax-ol相当,体内循环时间较Taxol明显延长;mPEG-APA-PTX是一种可自组装、载药量高、体内循环时间长的新型纳米前药。

Two amphiphilic prodrugs, mPEG-APA-PTX and mPEG-HDI-PTX, were prepared by conju- gating PEG monornethyl ether （mPEG） short chains to paclitaxel（PTX） via p-aminophenylacetic （APA） or hexamethylene diisocyanate （HDI） as linkers. The capability of self-assembling, the PTX release kinetics, the cytotoxicity and the life-time in plasma of them were characterized. Results showed that the prodrugs self-assembled into stable nanoparticles in aqueous solution with high drug loading content （280//00）. MPEG-HDI-PTX nanoparticles stayed stable in aqueous solution, but completely lost their cytotoxicity and were eliminated rapidly in plasma. While mPEG APA PTX nanoparticles released PTX slowly when pH = 7.4, their cytotoxicity was similar to Taxol and the nanoparticles had a remarkable longer blood cir- culation time than Taxol. In summary, the mPEG-APA-PTX was capable of self-assembly into high drug-loaded and long plasma circulating polymeric nanoparticles.