Effects of pluronic P85 unimers and micelles on drug permeability in polarized BBMEC and Caco-2 cells
Effects of pluronic P85 unimers and micelles on drug permeability in polarized BBMEC and Caco-2 cells
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DOI：
10.1023/a:1011942814300
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发表时间：
1998-10-01
影响因子：
3.7
通讯作者：
Kabanov, AV
中科院分区：
文献类型：
--
作者：
Batrakova, EV;Han, HY;Kabanov, AV
目的：以极化的牛脑微血管内皮细胞（BBMEC）单层作为血脑屏障的体外模型，以Caco-2单层作为肠上皮的体外模型，研究Pluronic P85嵌段共聚物（P85）对P糖蛋白（P-gp）依赖性探针罗丹明123（R123）转运的影响。使用Side-Bi-Side扩散池对融合细胞单层进行渗透性和细胞外排研究。在低于临界胶束浓度的浓度下，P85抑制BBMEC和Caco-2细胞单层的P-gp外排系统，导致R123的顶侧至基底侧渗透性增加。相反，在高浓度的P85下，药物掺入胶束中，进入细胞，然后再循环回到顶端，导致R123穿过细胞单层的转运减少。通过预先将P85与胰岛素偶联，BBMEC单层中胶束掺入的R123的顶侧至基底侧渗透性增加，表明修饰的胶束进行受体介导的转胞作用。Pluronic嵌段共聚物可增加脑微血管内皮细胞和肠上皮细胞的膜转运和跨细胞渗透性。这表明这些嵌段共聚物可用于设计制剂以增加所选药物的脑吸收和口服吸收。
Purpose, Using polarized bovine brain microvessel endothelial cells (BBMEC) monolayers as in vitro model of the blood brain barrier and Caco-2 monolayers as a model of the intestinal epithelium, the present work investigates the effects of Pluronic P85 block copolymer (P85) on the transport of the P-gycoprotein (P-gp)- dependent probe, rhodamine 123 (R123).Methods. The permeability and cell efflux studies are performed with the confluent cell monolayers using Side-Bi-Side diffusion cells.Results. At concentrations below the critical micelle concentration, P85 inhibits P-gp efflux systems of the BBMEC and Caco-2 cell monolayers resulting in an increase in the apical to basolateral permeability of R123. In contrast, at high concentrations of P85 the drug incorporates into the micelles, enters the cells and is then recycled back out to the apical side resulting in decrease in R123 transport across the cell monolayers. Apical to basolateral permeability of micelle-incorporated R123 in BBMEC monolayers was increased by prior conjugation of P85 with insulin, suggesting that modified micelles undergo receptor-mediated transcytosis.Conclusions. Pluronic block copolymers can increase membrane transport and transcellular permeability in brain microvessel endothelial cells and intestinal epithelium cells. This suggests that these block copolymers may be useful in designing formulations to increase brain and oral absorption of select drugs.