Transport of paclitaxel (Taxol) across the blood-brain barrier in vitro and in vivo
Transport of paclitaxel (Taxol) across the blood-brain barrier in vitro and in vivo
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DOI：
10.1172/jci200215451
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发表时间：
2002-11-01
影响因子：
15.9
通讯作者：
Fricker, G
中科院分区：
文献类型：
--
作者：
Fellner, S;Bauer, B;Fricker, G
静脉注射后，大脑中的紫杉醇浓度非常低。由于紫杉醇通过p-糖蛋白（p-gp）从某些肿瘤中排除，因此相同的机制可能会阻止紫杉醇进入大脑。在体外，使用BODIPYF 1-紫杉醇，通过共聚焦显微镜检查紫杉醇在大鼠脑毛细血管中的转运。蛋白质印迹和免疫组化染色表明，在孤立的内皮细胞，血管和组织的顶端表达的P-gp。BODIPY FL-紫杉醇向毛细血管腔中的分泌是特异性的和能量依赖性的。稳态管腔荧光显著超过细胞荧光，并被NaCN、紫杉醇和SDZ PSC-833（valspodar）（一种p-gp阻断剂）降低。白三烯C-4（LTC 4），一种Mrp 2-底物，没有影响。NBDL-环孢菌素（一种P-gp底物）的管腔蓄积被紫杉醇抑制。在体内，紫杉醇在裸鼠的脑、肝、肾和血浆中的水平在静脉注射后测定。与单药治疗相比，伐司泊达联合给药导致脑中紫杉醇水平升高。在脑内植入人U-118 MG胶质母细胞瘤的裸鼠中证明了治疗相关性。紫杉醇不影响肿瘤体积，紫杉醇（静脉内）和PSC 833（口服）联合给药使肿瘤体积减少90%。因此，p-gp是阻止紫杉醇进入大脑的重要障碍，抑制这种转运蛋白可使药物到达CNS内的敏感肿瘤。
Paclitaxel concentrations in the brain are very low after intravenous injection. Since paclitaxel is excluded from some tumors by p-glycoprotein (p-gp), the same mechanism may prevent entry into the brain. in vitro, paclitaxel transport was examined in capillaries from rat brains by confocal microscopy using BODIPY Fl-paclitaxel. Western blots and immunostaining demonstrated apical expression of p-gp in isolated endothelial cells, vessels, and tissue. Secretion of BODIPY Fl-paclitaxel into capillary lumens was specific and energy-dependent. Steady state luminal fluorescence significantly exceeded cellular fluorescence and was reduced by NaCN, paclitaxel, and SDZ PSC-833 (valspodar), a p-gp blocker. Leukotriene C-4 (LTC4), an Mrp2-substrate, had no effect. Luminal accumulation of NBDL-cyclosporin, a p-gp substrate, was inhibited by paclitaxel. In vivo, paclitaxel levels in the brain, liver, kidney, and plasma of nude mice were determined after intravenous injection. Co-administration of valspodar led to increased paclitaxel levels in brains compared to monotherapy. Therapeutic relevance was proven for nude mice with implanted intracerebral human U-118 MG glioblastoma. Whereas paclitaxel did not affect tumor volume, co-administration of paclitaxel (intravenous) and PSC833 (peroral) reduced tumor volume by 90%. Thus, p-gp is an important obstacle preventing paclitaxel entry into the brain, and inhibition of this transporter allows the drug to reach sensitive tumors within the CNS.