聚己内酯-紫杉醇高分子前药的合成及性能研究
收稿日期: 2015-01-20
网络出版日期: 2015-01-28
基金资助
项目受国家自然科学基金(Nos. 21274039, 81371123)、上海市浦江人才计划(No. 14PJD014)和上海市基础研究重点(Nos. 12JC1403000, 12JC1403100)资助.
Synthesis and Properties of the Poly(ε-caprolactone)-paclitaxel Prodrug
Received date: 2015-01-20
Online published: 2015-01-28
Supported by
Project supported by the National Natural Science Foundation of China (Nos. 21274039, 81371123), the Shanghai Pujiang Program (No. 14PJD014) and the Basic Research Key Program Project of Commission of Science and Technology of Shanghai (Nos. 12JC1403000, 12JC1403100).
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.
杜征臻 , 张琰 , 叶金海 , 徐衡 , 郎美东 . 聚己内酯-紫杉醇高分子前药的合成及性能研究[J]. 化学学报, 2015 , 73(4) : 349 -356 . DOI: 10.6023/A15010055
This study presents a paclitaxel (PTX) based polymeric prodrug (FCPTX) using functionalized Pluronic-b-poly(ε-caprolactone) bearing carboxyl groups [pluronic-b-poly(ε-caprolactone-co-6-carboxylic-ε-caprolactone), Pluronic-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 employed 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 nanomicellar 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 micellar core. The sustained in vitro release of PTX/FCPTX was due to that the forceful intermolecular interaction between conjugated 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 conjugated PTX was reduced due to that the 2'-OH of PTX was reacted and the drug activity was crippled. The PTX/FCPTX micelles revealed high antitumor activity due to the high cellular accumulation by micelle delivery. Subsequently, the great blood compatibility of FCPTX micelles and PTX/FCPTX micelles were obtained. All of the results demonstrated the use of the polymeric conjugated PTX as the core of the polymeric micelles afforded an ideal affinity site for free PTX and had a marvelous potential in combination chemotherapy.
Key words： ε-caprolactone; polymeric prodrug; paclitaxel; micelle
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