INTERACTIONS OF PLURONIC BLOCK-COPOLYMERS WITH BRAIN MICROVESSEL ENDOTHELIAL-CELLS - EVIDENCE OF 2 POTENTIAL PATHWAYS FOR DRUG ABSORPTION

Pluronic block copolymers have been previously reported to increase th e delivery of agents to the brain [Kabanov et al. (1992) J. Controlled Release 22, 141-158]. In the present study, primary cultured bovine b rain microvessel endothelial cells (BBMEC) were used as an in vitro mo del of the blood-brain barrier to examine the membrane interactions of Pluronic P85 (P85) and potential mechanisms for drug absorption. At c oncentrations below the critical micelle concentration (cmc), P85 enha nced the accumulation of the fluorescent probe rhodamine 123 (R123) in BBMEC through inhibition of P-glycoprotein (P-gp)-mediated drug efflu x. The effects of P85 on the cellular accumulation of R123 were also o bserved in KBv cells (P-gp positive) but not in human umbilical vein e ndothelial 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 affe cts the absorption of drugs in brain microvessel endothelial cells thr ough (1) inhibition of the P-gp-mediated drug efflux at low concentrat ions 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 dem onstrated by the inhibitory effects of the metabolic inhibitor 2-deoxy glucose.