双尾型表面活性剂mPEG-二硬脂酸酯的合成及其在胶束给药系统中的应用  

Synthesis of mPEG-distearate-based Double-tailed Surfactants and the Application in Micellar Drug Delivery System

作　　者：杨玄琳 徐晓珍 郝越 翁伟宇 YANG Xuanlin;XU Xiaozhen;HAO Yue;WENG Weiyu(Shanghai Key Lab.of New Drug Design,School of Pharmacy,East China University of Science and Technology,Shanghai 200237)

机构地区：[1]华东理工大学药学院,上海市新药设计重点实验室,上海200237

出　　处：《中国医药工业杂志》2022年第3期345-351,共7页Chinese Journal of Pharmaceuticals

摘　　要：本研究旨在合成聚乙二醇单甲醚(mPEG)链接二硬脂酸酯的双尾型表面活性剂,评估其作为载药胶束材料的潜力。选用相对分子质量为1000、2000和5000的mPEG,以(R)-3-氨基-1,2-丙二醇为连接臂,合成了3种mPEG-氧羰基-3-氨基-1,2-丙二醇二硬脂酸酯(mPEG-DS)。测得各mPEG-DS的临界胶束浓度均低于10μg/ml;20 mg/ml时的溶血率均小于5%;对多西他赛的增溶效果均优于同浓度的Tween-80,且随mPEG相对分子质量减小,聚合物对多西他赛的增溶效果增强。以mPEG_(1000)-DS和mPEG_(2000)-DS为材料制得的多西他赛胶束的粒径为(22.17±1.83)和(62.24±2.73)nm,几乎不带电荷,包封率均大于95%。以SD大鼠为动物模型进行药动学试验,结果显示mPEG_(2000)-DS载药胶束静注后的药动学行为与市售多西他赛注射液(泰索帝)相似,而mPEG_(1000)-DS载药胶束则呈现明显的长循环特征,表明mPEG-DS具有成为载药胶束材料的良好潜力。This study aims to synthesize double-tailed surfactants(DTS) composed of polyethylene glycol monomethyl ether(mPEG) and stearate and evaluate their applications in micellar drug delivery system.Three mPEG-oxycarbonyl-3-amino-1,2-propanediol distearates(mPEG-DSs) were synthesized by using (R)-3-amino-1,2-propanediol as the linker to connect stearate with mPEGs of different molecular weights(1 000,2 000,and 5 000).The critical micelle concentrations of three synthesized mPEG-DSs were lower than 10 μg/ml,and the hemolysis rates were less than 5% at 20 mg/ml of concentration.The solubilization effects of mPEG-DSs on docetaxel were better than that of Tween-80 at the same concentration,and their effects increased with decreasing molecular weight of mPEGs.The particle size of docetaxel-loaded micelles prepared with mPEG;-DS and mPEG;-DS were (22.17±1.83) and (62.24±2.73)nm,respectively.Both drug-loaded micelles exhibited neutral charge and high encapsulation efficiency(>95%).The pharmacokinetics was carried out with SD rats as animal models.After intravenous injection,the pharmacokinetic profiles of the docetaxel-loaded mPEG;-DS-based micelles were similar to those of the commercially available docetaxel injection(Taxotere).In contrast,the docetaxel-loaded mPEG;-DS-based micelles showed prolonged blood circulation time.In conclusion,the mPEG-DSs showed a good prospect for micellar drug delivery system application.

关 键 词：双尾型表面活性剂 聚乙二醇 硬脂酸酯 多西他赛 胶束 药动学 

分 类 号：R944.9[医药卫生—药剂学]