Interactions of pluronic block copolymers with brain microvessel endothelial cells: Evidence of two potential pathways for drug absorption
Interactions of pluronic block copolymers with brain microvessel endothelial cells: Evidence of two potential pathways for drug absorption
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DOI：
10.1021/bc970118d
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发表时间：
1997-09-01
影响因子：
4.7
通讯作者：
Kabanov, AV
中科院分区：
文献类型：
--
作者：
Miller, DW;Batrakova, EV;Kabanov, AV
先前已报道Pluronic嵌段共聚物增加药剂向脑的递送[Kabanov等人（1992）J. Controlled Release 22，141-158]。在本研究中，原代培养的牛脑微血管内皮细胞（BBMEC）被用作血脑屏障的体外模型，以检查Pluronic P85（P85）的膜相互作用和药物吸收的潜在机制。在低于临界胶束浓度（cmc）的浓度下，P85通过抑制P-糖蛋白（P-gp）介导的药物外排来增强荧光探针罗丹明123（R123）在BBMEC中的蓄积。在KBv细胞（P-gp阳性）中也观察到P85对R123细胞蓄积的影响，但在人脐静脉内皮细胞（P-gp阴性）中未观察到。与P85低于cmc的作用相反，用Pluronic胶束观察到的R123吸收增强是短暂的，不依赖于P-gp。在P-gp阳性细胞（脑微血管内皮细胞和KBv）和P-gp阴性细胞（人脐静脉内皮细胞）中均观察到R123蓄积的一过性增加。因此，P85似乎通过（1）在低浓度共聚物下抑制P-gp介导的药物外排和（2）在较高浓度共聚物下增加囊泡转运来影响脑微血管内皮细胞中药物的吸收。此外，P85与脑内皮细胞的相互作用似乎是能量依赖性的，如代谢抑制剂2-脱氧葡萄糖的抑制作用所证明的。
Pluronic block copolymers have been previously reported to increase the delivery of agents to the brain [Kabanov et al. (1992) J. Controlled Release 22, 141-158]. In the present study, primary cultured bovine brain microvessel endothelial cells (BBMEC) were used as an in vitro model of the blood-brain barrier to examine the membrane interactions of Pluronic P85 (P85) and potential mechanisms for drug absorption. At concentrations below the critical micelle concentration (cmc), P85 enhanced the accumulation of the fluorescent probe rhodamine 123 (R123) in BBMEC through inhibition of P-glycoprotein (P-gp)-mediated drug efflux. The effects of P85 on the cellular accumulation of R123 were also observed in KBv cells (P-gp positive) but not in human umbilical vein endothelial cells (P-gp negative). In contrast to the effects with P85 below the cmc, the enhanced absorption of R123 observed with Pluronic micelles was transient and not dependent on P-gp. A transient increase in R123 accumulation was observed in both P-gp positive cells (brain microvessel endothelial cells and KBv) and P-gp negative cells (human umbilical vein endothelial cells). Therefore, it appears that P85 affects the absorption of drugs in brain microvessel endothelial cells through (1) inhibition of the P-gp-mediated drug efflux at low concentrations of the copolymer and (2) increased vesicular transport at higher concentrations of the copolymer. Furthermore, both interactions of P85 with the brain endothelial cells appear to be energy-dependent as demonstrated by the inhibitory effects of the metabolic inhibitor 2-deoxyglucose.