多西他赛pH敏感型聚(2-乙基-2-噁唑啉)-聚(D,L-丙交酯)自组装胶束的制备及其性质

Preparation and characteristics of docetaxel pH-sensitive poly(2-ethyl-2-oxazoline)-poly(D,L-lactide) self-assembly micelles

目的利用两亲性嵌段共聚物聚(2-乙基-2-噁唑啉)-聚(D,L-丙交酯)[poly(2-ethyl-2-oxazo-line)-poly(D,L-lactide),PEOz-PDLLA]的自组装性能制备pH敏感型多西他赛胶束,并对其相关性质进行考察。方法运用阳离子开环聚合反应得到PEOz-PDLLA,通过FITR、1H-NMR和凝胶色谱法对其结构进行表征,采用电位滴定法测定共聚物pKa,应用荧光探针技术确定临界胶束浓度(criticalm icelle concentration,CMC)。动态光散射法和Zeta电位测试仪测定胶束的粒径和Zeta电位。以薄膜分散法包载多西他赛,并用透析法研究载药胶束的体外释放度。结果PEOz-PDLLA的亲水/疏水段分子质量比值为0.76,pKa为6.41,CMC为0.8×10-3g.L-1。载药胶束包封率为94.9%、载药量质量分数为8.7%、平均粒径为(35.3±4.9)nm、Zeta电位为(25.51±2.14)mV,在pH5.0的释放介质中释药速度加快。结论PEOz-PDLLA嵌段共聚物可自组装形成胶束,高效包载多西他赛,体外释放具有pH敏感性。

Objective To prepare pH-sensitive docetaxel micelles based on the property of self-assembly of poly （2-ethyl-2-oxazoline） -poly （ D, L-lactide） （PEOz-PDLLA） and study their pharmaceutical properties.Methods PEOz-PDLLA was synthesized by cationic ring-opening polymerization and its structure was characterized by FTIR, ^1HNMR and gel permeation chromatography. Potentiometric titration and fluorescent probe technique were empolyed to measure the pKa and critical mieelle concentration （CMC）of the block polymer, respectively. The diameter of micelle was determined by dynamic light scattering. The micelle Zeta potential was measured by Zeta potential analyzer. Docetaxel was encapsulated by film-dispersion method. The in vitro drug releasing behavior was studied by dialysis. Results The molecular weight ratio of hydro- philic/hydrophobic segmertt of PEOz-PDLLA was 0.76. Its pKa and CMC was 6.41 and 0.8×10^-3g·L^-1, respectively. The entrapment efficiency of micelles reached 94.9%, and the drug-loaded amount was 8.7%. The mean diameter of micelles was（35.3±4.9）nm with a Zeta potential of（25.51 ±2.14） mV. The drug releasing of micelles was accelerated in the medium with a pH of 5.0. Conclusions PEOz-PDLLA can form micelles by its self-assembly behavior. The micelles posses the ability of entrapping docetaxel effectively and the performance of drug releasing in vitro is pH-sensitive.