PEG化羟甲基小白菊内酯抗肿瘤前药纳米颗粒的制备及性能  

Preparation and Property of PEGylated Melampomagnolide B Prodrug Nanoparticles for Cancer Therapy

作　　者：屈文豪 杨全军[2] 黄平[1] 黄卫[1] 颜德岳[1] QU Wenhao;YANG Quanjun;HUANG Ping;HUANG Wei;YAN Deyue(State Key Laboratory of Metal Matrix Composite,School of Chemistry and Chemical Engineering,Shanghai Jiao Tong University,Shanghai 200240,China;Department of Pharmacy,Shanghai Jiao Tong University Affiliated Sixth People's Hospital,Shanghai 200233,China)

机构地区：[1]上海交通大学化学化工学院,金属基复合材料国家重点实验室,上海200240 [2]上海交通大学附属第六人民医院药剂科,上海200233

出　　处：《功能高分子学报》2020年第3期275-283,共9页Journal of Functional Polymers

基　　金：2016年科技部国家重点研发计划项目(2016YFA0201500);国家自然科学基金青年项目(21702097)。

摘　　要：通过酯化反应将羧基聚乙二醇单甲醚(mPEG10-COOH)与羟甲基小白菊内酯(MMB)进行偶联得到两亲性前药mPEG10-MMB,其化学结构通过核磁共振(NMR)和液相色谱-质谱(LCMS)联用表征得到确认。mPEG10-MMB的两亲性分子结构使其在水中可自组装形成纳米颗粒,其临界胶束质量浓度为7.7μg/mL。动态光散射(DLS)测试结果表明:mPEG10-MMB前药纳米颗粒的粒径约为120.3 nm,且粒径分布较窄。透射电子显微镜(TEM)测试结果表明:mPEG10-MMB前药纳米颗粒呈球形,粒径约为108.5 nm。以尼罗红为荧光探针负载到mPEG10-MMB前药纳米颗粒中,采用流式细胞仪和激光共聚焦显微镜(CLSM)检测了mPEG10-MMB前药纳米颗粒进入肿瘤细胞的情况,结果表明,mPEG10-MMB前药纳米颗粒主要通过内吞方式进入宫颈癌肿瘤细胞。MTT评估结果表明,mPEG10-MMB前药纳米颗粒比游离MMB具有更好的抗肿瘤活性,但对正常细胞的毒性相对较低。Melampomagnolide B(MMB)is one of the parthenolide(PTL)derivatives with high anticancer activity to various tumors.However,its application in the clinic is limited due to its poor water solubility.To overcome this problem,an amphiphilic prodrug is synthesized from carboxyl polyethylene glycol monomethyl ether(mPEG10-COOH)and MMB through an esterification reaction.The chemical structure of mPEG10-MMB is confirmed by nuclear magnetic resonance(NMR)and liquid chromatography-mass spectrometry(LC-MS).The amphiphilic prodrug mPEG10-MMB can self-assemble in water with the critical micelle mass concentration of 7.7μg/mL and the size/morphology of its assemblies is characterized by dynamic light scattering(DLS)and transmission electron microscopy(TEM).The DLS result indicates that an averaged size of mPEG10-MMB nanoparticles is about 120.3 nm with a narrow distribution.The TEM image exhibits that mPEG10-MMB can self-assemble into spherical nanoparticles with an average diameter of 108.5 nm.Nile red(NR)is used as the fluorescent probe and loaded in mPEG10-MMB prodrug nanoparticles.The flow cytometry and confocal laser scanning microscope(CLSM)are used to evaluate the cell uptake of mPEG10-MMB prodrug nanoparticles.The results demonstrate that mPEG10-MMB prodrug nanoparticles can be internalized by HeLa cells efficiently through the endocytosis mechanism.In vitro cytotoxicity of mPEG10-MMB prodrug nanoparticles is evaluated against HeLa cells and BRL-3A cells by MTT assay.The result demonstrates that mPEG10-MMB prodrug nanoparticles have higher cytotoxicity to cancer cells compared to that of free MMB,but relatively lower cytotoxicity to normal cells.

关 键 词：羟甲基小白菊内酯 聚乙二醇 前药 纳米颗粒 抗肿瘤 

分 类 号：O63[理学—高分子化学]