The micelles formed by poly(ethylene oxide)-poly(propylene oxide) block copolymers (Pluronic) have been used to enhance the transport of certain agents to the brain in vivo. The mechanism for the enhanced brain delivery observed with these systems is not known. The objective of this proposal is to determine the mechanisms through which Pluronic copolymers enhance the transport of drugs across the blood brain barrier (BBB). The hypothesis being evaluated is that enhanced brain transport of drugs with Pluronic copolymers can occur through either effects of the polymer on P-glycoprotein (P-gp) drug efflux systems present in the BBB or alterations in the vesicular transport and cellular processing in the BBB. It is further hypothesized that the requirements for Pluronic interactions with drug efflux and vesicular transport systems in the BBB will be different and thus allow for the optimization of Pluronic to favor one route over another. Using primary cultured bovine brain microvessel endothelial cells (BBMEC) as an in vitro model of the BBB and brain microdialysis in the freely moving awake rat as an in vivo model of the BBB, the Specific Aims of the proposed studies are to : (1) characterize the effects of Pluronic copolymers on drug uptake pathways in BBMEC monolayers; (2) characterize the effects of Pluronic copolymers on the intracellular processing and transcellular permeability of drug in BBMEC monolayers; (3) examine the effects of drug targeting vectors conjugated to Pluronic micelles on drug processing and permeability in BBMEC monolayers; (4) compare the effects of Pluronic copolymers on drug permeability in BBB in vitro and in vivo. Studies on Specific Aims 1-3 will evaluate the cellular transport of the P-gp substrate, rhodamine 123, and its non-P-gp dependent analog, rhodamine 110, to discriminate transport mechanisms and to identify the Pluronic systems that enhance drug permeability in brain microvessel endothelial cells. The Pluronic compositions identified in these experiments will be validated in Specific Aim 4 for brain delivery of anthracycline antibiotic doxorubicin using both in vitro and in vivo models. The information obtained from this study will allow for the optimization of Pluronic systems for the delivery of drugs to the brain.
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