阿霉素隐形脂质体的研制及其在小鼠体内的组织分布

 目的:研制出包封率高,逃避体内网状内皮系统捕获的“隐形"(stealth)脂质体并考察其在生物体内的组织分布?方法:以化学梯度法包封脂质体,用两亲性聚乙二醇-二硬脂酰磷脂酰乙醇胺(PEG-DSPE)对脂质体膜进行修饰以制备隐形脂质体;用HPLC-UV法测定给药后小鼠体内组织中的药物浓度?结果:制备的阿霉素隐形脂质体包封率达97%以上;与普通脂质体及游离的阿霉素相对照,隐形脂质体在血液中循环时间显著地延长,血药浓度-时间曲线下面积(AUC)显著增加,三种制剂在小鼠的心、肝、脾、肺、肾组织中的分布特性有不同程度的改变?结论:这种化学梯度法可以较大地提高包封率?隐形脂质体血液AUC增加,可延长药物在体内循环时间;心脏组织分布浓度低,可降低心脏毒性?

Development of the stealth doxorubicin liposomes and tissue distribution in mice

OBJECTIVES:To develop the stealth liposomes which may have high entrapment efficiency and result in a pronounced increase in blood circulation time with a parrallel decrease in the uptake by reticuloendothelial system (RES); to observe the tissue distribution of the newly developed liposomes in mice. METHODS:The chemical gradients method was used to load amphipathic doxorubicin into liposomes. The amphipathic PEG DSPE (Polyethylene glycol distearoyl phosphatidylethanolamine) was added to modify the quality of liposome membrane. The high performance liquid chromatography with UV detector was utilised for the determination of doxorubicin concentrations in mice tissues.RESULTS: This chemical approach was applied to encapsulate doxorubicin into the liposomes at very high efficiency (>97%). After tail iv injection, the blood exposure time of stealth liposomes and the area under blood drug concentration time curve were pronouncedly increased, compared with the regular liposomes group and the free doxorubicin group,respectively. The tissue distributions of the three formulations in mice were changed differently.CONCLUSIONS:The chemical gradient method can highly increase the entrapment efficiency of amphipathic weak base such as doxorubicin into liposomes. The AUC of stealth liposomes was increased and the long circulation time can be reached after modification of lipid membrane with PEG DSPE. The concentrations of doxorubicin in heart tissues were decreased by the liposomes, thus heart toxicity of doxorubicin may be reduced.