【摘要】 目的研究用靶向功能基Angiopep-2修饰多柔比星(DOX)脂质体,增加药物在脑胶质瘤部位递送。方法薄膜分散法制备空白脂质体,靶向功能基Angiopep-2通过膜材料中DSPE-PEG-MAL连接对其进行修饰,DOX作为模型药物通过pH梯度法装载,制得Angiopep-2修饰脂质体(Dox-AL)。体外实验中,初步考察了大鼠C6细胞对游离DOX、普通DOX脂质体(DOX-NL)和DOX-AL的摄取。C6脑胶质瘤模型小鼠尾静脉注射DOX、DOX-NL和DOX-AL,LC-MS/MS检测小鼠血浆、脑和肿瘤组织DOX浓度。结果 DOX脂质体粒径约为100 nm,包封率99%;大鼠C6细胞对DOX-AL的摄取高于DOX-NL;C6脑胶质瘤模型小鼠iv给予剂量为5 mg.kg-1DOX、DOX-NL和DOX-AL后,3组制剂药物在体内快速分布,较缓慢消除,均符合三室模型。与DOX相比,脂质体制剂能显著延长DOX血液循环时间,增加药物入脑机会;DOX-AL在脑和肿瘤中的AUC0-t分别是DOX-NL的2.92和7.76倍。结论 Angiopep-2修饰的脂质体作为载体可通过受体介导的方式促进药物胶质瘤靶向递送。更多还原

【Abstract】 OBJECTIVE To investigate the possibility of using doxorubicin-loaded liposomes modified with Angiopep-2 as the targeted carriers to achieve increased accumulation in glioma.METHODS The liposome was prepared by film hydration,and the maleimides of DSPE-PEG-MAL on the liposome surface conjugated with the Angiopep-2 covalently.By pH gradient drug loading,Doxorubicin liposome(DOX-AL)was obtained at last.Using rat glioma cells(C6)as cell model of in vitro study,the drug delivery characteristics of DOX-AL to glioma were investigated,and the results would be compared with DOX and the normal doxorubicin liposome(DOX-NL).DOX,DOX-NL,and DOX-AL were injected intravenously to glioma implanted mice.The doxorubicin concentration in plasma,brain,and tumor were investigated using LC-MS/MS method.RESULTS The volume based particle size of the liposome was about 100 nm and the encapsulation efficiency was above 99%.The qualitative uptake results demonstrated that the uptake of DOX-AL was more than that of DOX-NL.The pharmacokinetics results after DOX,DOX-NL,and DOX-AL were injected intravenously at a dose of 5 mg·kg-1 to glioma implanted mice showed that DOX,DOX-NL,and DOX-AL were fast distributed and slowly eliminated,which fitted with three-compartment model.Compared with DOX,doxorubicin liposomes significantly prolonged circulation time of drug in vivo and increased its brain uptake,AUC0-t of DOX-AL in the brain and tumor were 2.92 and 7.76 times those of DOX-NL.CONCLUSION Angiopep-2 modified doxorubicin liposome could be as the targeted carriers to facilitate the delivery of the drugs to glioma by receptor-mediated way.更多还原