脑靶向多柔比星胶束的制备及体外性质研究

Preparation and in vitro Properties Study of Brain-targeting Doxorubicin Micelles

目的:制备脑靶向多柔比星胶束,并评价其体外理化性质。方法:合成葡萄糖修饰的泊洛沙姆P105衍生物(葡萄糖-泊洛沙姆P105),考察其氢核磁共振(1H-NMR)图谱,计算葡萄糖的偶联率。用透析法以葡萄糖-泊洛沙姆P105制备脑靶向多柔比星胶束,用单因素法考察处方中多柔比星的投药量、二甲基亚砜(DMSO)与水相的比例对胶束包封率和载药量的影响;考察所制胶束的粒径、Zeta电位、形貌、体外释药情况;以星型胶质细胞和小鼠脑微血管内皮(BMVECs)细胞模拟体外血脑屏障(BBB),比较多柔比星水溶液、多柔比星普通胶束、多柔比星胶束透过BBB的转运率。结果:合成的葡萄糖-泊洛沙姆P105的葡萄糖偶联率为88.7%。随着多柔比星投药量和DMSO有机相比例的增加,包封率和载药量均呈先升高后降低的趋势,其中多柔比星为7 mg、DMSO与水相的体积比为0.10∶1时包封率和载药量最好;所制胶束的平均粒径为(26.7±5.4)nm,Zeta电位为(-6.48±0.64)m V,透射电镜照片显示呈球状;体外释药动力学符合Weibull方程;多柔比星胶束的BBB转运率明显高于多柔比星普通胶束。结论:成功制得具有脑靶向功能的多柔比星胶束。

OBJECTIVE： To prepare the brain-targeting doxorubicin micelles and evaluate its physical and chemical properties in vitro. METHODS： The glucose-mediated poloxamer P105 derivatives （glucose-poloxamer P105） was synthesized, its H-NMR was investigated and coupling rate was calculated. Glucose-poloxamer P105 brain-targeting doxorubicin micelles were prepared by dialysis. The effect of doxorubicin dosage and the proportion of DMSO and water phase on micelles encapsulation efficiency and drug loading amount was investigated with single factor. The diameter, the Zeta potential and appearance of micelles were investi- gated. Astrocytes and mice brain microvascular endothelial cells （BMVECs） were used to construct blood-brain barrier （BBB） in vi- tro to compare the transport ratio of doxorubicin solution, doxorubicin ordinary micelles and doxorubicin micelles through BBB. RESULTS： The glucose coupling rate of synthesis glucose-poloxamer P105 was 88.7 %. As the drug feed and DMSO organic phase ratio increased, the entrapment rate and drug-loading amount were increased first and then decreased, especially best in the volume ratio of DMSO and water phase was 0.10 ： 1 and 7 mg doxorubicin. The micelles had a mean diameter of （26.7 ± 5.4） nm, and Zeta potential was （ -6.48 ± 0.64） mV. TEM images showed spherical micelles doxorubicin. The drug release kinetics in vitro of mi- celles met the Weibull equation. In the BBB model, drugs transport ratio of glucose-mediated doxorubicin micelles was significantly higher than ordinary ones. CONCLUSIONS： The brain-targeting doxorubicin micelle is obtained successfully.