p-Hydroxybenzoic acid (p-HA) modified polymeric micelles for brain-targeted docetaxel delivery  

作　　者：ZHANG ZhiXin WEI XiaoLi ZHANG XiaoYu LU WeiYue 

机构地区：[1]Department of Pharmaceutics, School of Pharmacy, Fudan University [2]Key Laboratory of Smart Drug Delivery (Fudan University), Ministry of Education & The Chinese People's Liberation Army [3]State Key Laboratory of Molecular Engineering of Polymers (Fudan University)

出　　处：《Chinese Science Bulletin》2013年第21期2651-2656,共6页

基　　金：supported by the National Basic Research Program of China (2013CB932500);the National Natural Science Foundation of China(81273458);the Key New Drug Creation Program (2012ZX09304004)

摘　　要：Chemotherapies for brain diseases have been hampered due to the inability of transport of drug across the blood-brain barrier (BBB). In order to overcome the barrier, p-hydroxybenzoic acid (p-HA), a small molecule of benzamide analogue, was used as a ligand for brain-targeted drug delivery. The p-HA was conjugated to PEG-DSPE to form p-HA-PEG-DSPE. Docetaxel-loaded polymeric micelles were prepared by a thin-film hydration method using methoxy-poly(ethylene glycol)-distearoylphosphatidyl- ethanolamine (mPEG 2000 -DSPE) as a carrier and the p-HA-PEG-DSPE as a brain targeted material. The prepared micelles showed spherical with a mean diameter of (18±3) nm. Encapsulation efficiency and drug loading were (83.49±1.3)%, (7.7±1.2)% for un- modified micelles and (80.65±1.6)%, (7.47±1.8)% for p-HA-modified micelles, respectively. In vitro cellular uptake experiments showed that the p-HA-modified micelles increased BCECs cellular uptake by 1.2 times compared to the unmodified micelles. Ex vivo near-infrared fluorescence imaging showed that brain uptake of the p-HA-modified micelles was 1.3-1.8 times higher than that of the unmodified micelles. In vitro cytotoxicity assay against glioblastoma cell U87 MG showed that inhibition rate of the p-HA-modified micelles increased by 1.2 times compared to that of the unmodified micelles and 1.7 times compared to that of DTX. Survival time of nude mice bearing intracranial glioblastoma showed that the lifetime of saline group, Taxotere group, mPEG-DSPE/DTX micelles group and p-HA-PEG-DSPE/DTX micelles group was 22, 27, 32 and 45.8 d, representively, which indicated that anti-glioblastoma activity of DTX could be significantly enhanced by the p-HA-modified polymeric micelles. These results demonstrated that the p-HA-modified micelles could be a promising brain-targeted drug delivery system for hydrophobic drugs against glioblastoma.Chemotherapies for brain diseases have been hampered due to the inability of transport of drug across the blood-brain barrier （BBB）. In order to overcome the barrier, p-hydroxybenzoic acid （p-HA）, a small molecule of benzamide analogue, was used as a ligand for brain-targeted drug delivery. The p-HA was conjugated to PEG-DSPE to form p-HA-PEG-DSPE. Docetaxel-loaded polymeric micelles were prepared by a thin-film hydration method using methoxy-poly（ethylene glycol）-distearoylpbosphatidyl- ethanolamine （mPEG2000-DSPE） as a cartier and the p-HA-PEG-DSPE as a brain targeted material. The prepared micelles showed spherical with a mean diameter of （18±3） nm. Encapsulation efficiency and drug loading were （83.49±1.3）%, （7.7±1.2）% for un- modified micelles and （80.65±1.6）%, （7.47±1.8）% for p-HA-modified micelles, respectively. In vitro cellular uptake experiments showed that the p-HA-modified micelles increased BCECs cellular uptake by 1.2 times compared to the unmodified micelles. Ex vivo near-infrared fluorescence imaging showed that brain uptake of the p-HA-modified micelles was 1.3-1.8 times higher than that of the unmodified micelles. In vitro cytotoxicity assay against glioblastoma cell U87 MG showed that inhibition rate of the p-HA-modified micelles increased by 1.2 times compared to that of the unmodified micelles and 1.7 times compared to that of DTX. Survival time of nude mice bearing intracranial glioblastoma showed that the lifetime of saline group, Taxotere group, mPEG-DSPE/DTX micelles group and p-HA-PEG-DSPE/DTX micelles group was 22, 27, 32 and 45.8 d, representively, which indicated that anti-glioblastoma activity of DTX could be significantly enhanced by the p-HA-modified polymeric miceUes. These results demonstrated that the p-HA-modified micelles could be a promising brain-targeted drug delivery system for hydrophobic drugs against glioblastoma.

关 键 词：聚合物胶束 改性聚合物 对羟基苯甲酸 多西紫杉醇 脑疾病 靶向给药系统 细胞摄取 胶质细胞 

分 类 号：R96[医药卫生—药理学]