Brain drug delivery of small molecules using immunoliposomes
Brain drug delivery of small molecules using immunoliposomes
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DOI：
10.1073/pnas.93.24.14164
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发表时间：
1996-11-26
影响因子：
11.1
通讯作者：
Pardridge, WM
中科院分区：
文献类型：
--
作者：
Huwyler, J;Wu, DF;Pardridge, WM
免疫脂质体引入偶联程序，其允许巯基化抗体与用PEG空间稳定的马来酰亚胺接枝的85-nm脂质体偶联，从而将抗体偶联至PEG偶联的接头脂质的末端，没有观察到携带[H-3]柔红霉素的PEG缀合的脂质体的脑摄取，然而，携带[H-3]柔红霉素的免疫脂质体的脑靶向是由针对大鼠转铁蛋白受体的OX 26单克隆抗体介导的，其在体内选择性地富集在构成血脑屏障的脑微血管内皮上。每个脂质体偶联30个0X 26抗体导致最佳的脑递送，在较高的抗体密度下观察到递送的饱和，在24小时内测定免疫脂质体的脑水平揭示了免疫脂质体在脑组织中积累，在与小鼠IgG（2a）同种型对照偶联的免疫脂质体中未观察到免疫脂质体的脑靶向。共注射游离OX 26饱和血浆清除免疫脂质体。由于单个脂质体可携带大于或等于10，000个药物分子，因此PEG缀合的免疫脂质体的使用将单克隆抗体的药物携带能力增加多达4个对数数量级。总之，通过使用基于免疫脂质体的药物递送系统实现了特异性0X 26介导的柔红霉素靶向大鼠脑。
Immunoliposomes (antibody-directed liposomes) were used in the present study for delivery of the antineoplastic agent daunomycin to the rat brain, A coupling procedure was Introduced, which allows conjugation of a thiolated antibody to maleimide-grafted 85-nm liposomes sterically stabilized with PEG, Antibody was thereby coupled to the terminal end of a PEG-conjugated linker lipid, No brain uptake of PEG-conjugated liposomes carrying [H-3]daunomycin was observed, However, brain targeting of immunoliposomes carrying [H-3]daunomycin was mediated by the OX26 monoclonal antibody to the rat transferrin receptor, which is selectively enriched at the brain microvascular endothelium that comprises the blood-brain barrier in vivo. Coupling of 30 OX26 antibodies per liposome resulted in optimal brain delivery, Saturation of delivery was observed at higher antibody densities, Determination of brain levels of immunoliposomes over 24 h revealed that immunoliposomes accumulate in brain tissue, Brain targeting of immunoliposomes was not observed in immunoliposomes conjugated with a mouse IgG(2a) isotype control, In addition, coinjection of free OX26 saturated plasma clearance of immunoliposomes. Since a single liposome may carry greater than or equal to 10,000 drug molecules, the use of PEG-conjugated immunoliposomes Increases the drug carrying capacity of the monoclonal antibody by up to 4 logarithmic orders in magnitude, In summary, specific OX26-mediated targeting of daunomycin to the rat brain was achieved by the use of an immunoliposome-based drug delivery system.