聚己内酯-紫杉醇高分子前药的合成及性能研究  

Synthesis and Properties of the Poly(ε-caprolactone)-paclitaxel Prodrug

作　　者：杜征臻 张琰[1] 叶金海[2] 徐衡[3] 郎美东[1] 

机构地区：[1]上海市先进聚合物材料重点实验室超细材料制备与应用教育部重点实验室华东理工大学材料科学与工程学院,上海200237 [2]南京医科大学口腔医学院,南京210029 [3]安徽省石油化工新材料协同创新中心安庆师范学院化学化工学院,安庆246011

出　　处：《化学学报》2015年第4期349-356,共8页Acta Chimica Sinica

基　　金：国家自然科学基金(Nos.21274039;81371123);上海市浦江人才计划(No.14PJD014);上海市基础研究重点(Nos.12JC1403000;12JC1403100)资助~~

摘　　要：利用侧链带有羧基的官能化两亲性聚己内酯基共聚物Pluronic-b-poly(ε-caprolactone-co-6-carboxylic-ε-caprolactone)[Pluronic-b-P(CL-co-CCL),FC]为底物,与紫杉醇(PTX)反应得到了一系列PTX的聚合物前药FCPTX.通过核磁共振(1H NMR)和高效液相色谱(HPLC)表征了聚合物前药结构并分析了前药中的PTX接枝率.通过聚合物前药胶束进一步物理包载PTX,得到载有PTX的聚合物前药胶束PTX/FCPTX,其载药量和包封率随着前药FCPTX中的PTX接枝率的增加而提高.利用荧光光谱(FS)、透射电镜(TEM)和粒径分析仪(DLS)表征了胶束的临界胶束浓度(CMC),形态和粒径.体外细胞评价表明,聚合物前药FCPTX具有较高的胞内累积量和良好的血液相容性、能有效降低紫杉醇的药物毒性.作为一种优秀的药物载体,聚合物前药FCPTX在联合化疗领域有着较大的应用潜力.This study presents a paclitaxel （PTX） based polymeric prodrug （FCPTX） using functionalized Pluron- ic-b-poly（e-caprolactone） bearing carboxyl groups [pluronic-b-poly（ε-caprolactone-co-6-carboxylic-ε-caprolactone）, Pluron- ic-b-P（CL-co-CCL）, FC] as the substrate by a dicyclohexylcarbodiimide/4-dimethylaminopyridine-catalyzed （DCC/DMAP-catalyzed） esterification reaction. High Performance Liquid Chromatography （HPLC） and 1H NMR were em- ployed together to prove the successful reaction and confirmed the structure and composition of FCPTX. The result revealed that the 2＇-OH of PTX participated in reaction and the PTX content in FCPTX was up to 18.3 wt%. The polymeric prodrug could self-assemble into micelles via an emulsion/solvent evaporation technique. Furthermore, the micelle was used as the nanomicel- lar carrier for delivery of free PTX. TEM and DLS were used to study the size and morphologies of the FCPTX micelles and PTX-loaded FCPTX （PTX/FCPTX） micelles. The results demonstrated that the two micelles were spherical spheres with narrow distribution and the size of PTX/FCPTX micelles was larger than that of FCPTX micelles due to the micellar core was enlarged by the loaded drug. The drug loading content （DLC） and drug loading efficiency （DLE） demonstrated that the great drug loading capability of FCPTX for free PTX which could be attributed to the fact that the excellent compatibility between drug and micel- lar core. The sustained in vitro release of PTX/FCPTX was due to that the forceful intermolecular interaction between conjugat- ed PTX on the polymer and the encapsulated PTX, also, the forceful intermolecular interaction led to the high residual of PTX （only 33.0% total release after 72 h at pH 7.4）. However, in the lower pH environment, the drug release was accelerated due to hydrolysis of ester bond and disaggregation of micelles. In vitro antitumor experiments showed that the cytotoxicity of the con- jugated PTX was reduced due to that the 2＇-OH of PTX w

关 键 词：己内酯 聚合物前药 紫杉醇 胶束 

分 类 号：O633.14[理学—高分子化学] TQ460.1[理学—化学]