一种还原响应性紫杉醇胶束的制备与性能

Preparation and Properties of Redox-Responsive Paclitaxel Micelles

首先,以甲氧基聚乙二醇(mPEG)为大分子引发剂,以辛酸亚锡为催化剂使D,L-丙交酯开环聚合,得到共聚物甲氧基聚乙二醇-聚乳酸(mPEG-PLA);然后,在该共聚物的末尾端进行羟基树枝化并接枝硫辛酸(LA),制备了可交联聚合物mPEG-PLA-(LA)4。采用核磁共振氢谱(1 H-NMR)和凝胶渗透色谱(GPC)对聚合物的结构和分子量进行了表征。进一步采用薄膜水化法制备了包载紫杉醇的交联共聚物胶束,并利用动态光散射(DLS)和透射电镜(TEM)对胶束结构进行了表征,采用动物实验评价了载药胶束的抑瘤效果。结果表明:胶束的平均粒径为34.0nm,结构规整。相比于未交联胶束,交联胶束具有更好的稳定性与还原响应性,抑瘤效果提高显著。

A novel disulfide cross-linked redox-sensitive lipoic acid dendronized methoxy polyethylene glycol-polylactide block copolymer(mPEG-PLA-(LA)4) was successfully prepared.Firstly,methoxy polyethylene glycol-polylactide(mPEG-PLA) was synthesized by a ring opening polymerization of D,L -lactide using methoxy polyethylene glycol(mPEG) as a macroinitiator and stannous octoate(Sn(Oct)2) as the catalyst.Then,mPEG-PLA-(OH)4 was obtained by reaction of mPEG-PLA with acetonide-2,2-dimethylol propanoic anhydride(Ac-DMPA) and deprotection of the terminal acetonide groups.Finally,lipoic acid terminated methoxy polyethylene glycol-polylactide block copolymer(mPEG-PLA-(LA)4) was synthesized and paclitaxel-loaded mPEG-PLA-(LA)4 micelles were prepared by solid dispersion-thin film hydration method.The structures and molecular weights of the polymers were characterized by nuclear magnetic hydrogen spectrum(^1H-NMR) and gel permeation chromatography(GPC).Transmission electron microscope(TEM) and dynamic light scattering(DLS) were used to investigate the morphology and size distribution of the micelles.The results show that mPEG-PLA-(LA)4 micelles have spherical structure with average diameter of 34.0nm.Besides,the in vitro release behavior of paclitaxel-loaded mPEG-PLA-(LA)4 micelles was determined by a modified dialysis method.Compared with mPEG-PLA micelles,mPEG-PLA-(LA)4 micelles have better stability and redox-responsive.The in vivo results reveal that mPEG-PLA-(LA)4 micelles reduce the acute toxicity in mice and show improved anti-tumor efficacy compared with mPEG-PLA micelles.All these indicate that mPEG-PLA-(LA)4 micelles are highly promising drug delivery system for clinical application.