Abstract Dr. A. Rice
Title of Project Assessment of Drug Uptake and Permeability Properties of Novel Anticancer Agents in the Brain
Abstract The blood-brain barrier (BBB) effectively prevents microtubule-stabilizing drugs from readily entering the central nervous system (CNS). A major limiting factor for microtubule (MT)-stabilizing drug permeation across the BBB is the active efflux back into the circulation by the overexpression of the multidrug resistant gene product (MDR1) or P-glycoprotein (P-gp). This study focuses on strategies to overcome P-gp-mediated efflux of taxol analogues, MT-stabilizing agents that could be used to treat brain tumors and, potentially, neurodegenerative diseases such as Alzheimer’s disease. However, taxol is a strong P-gp substrate, which limits its distribution across the BBB and therapeutic potential in the CNS. We hypothesize that taxane analogues can be prepared that elude the MDR transporter by altering and/or deleting functional groups that are recognition elements for the transporter. Also, it is hypothesized that analogues produced by covalently linking known vectors with carriers in the endothelial cells of the BBB will be delivered to the brain with the aid of these transport systems. Our studies demonstrate the feasibility of making small chemical modifications to taxol to generate analogues with reduced affinity for P-gp but with retention of MT-stabilizing properties, (e.g., a taxane that may reach and treat therapeutic targets in the CNS). The specific aims of this project will be to: (1) successfully establish the primary cell culture of bovine brain microvessel endothelial cells (BBMECs) to be used for high-throughput screening of anticancer drugs and characterize active, functional transporter systems present in the brain; (2) determine the mechanistic pathway of a newly synthesized taxane analogue that evades P-gp and accumulates in the brain by assessing the transcellular permeability properties in diffusion experiments across BBMEC monolayers; and (3) determine uptake and permeability properties of other novel anticancer drugs in the brain to assess whether chemical modifications will enhance their brain availability. This project focuses on the specific functions of the mechanisms controlling the BBB permeation of anticancer drugs. Knowledge of these mechanisms should lead to other strategies that may be employed to enhance therapeutic delivery of pharmaceuticals to the brain.
Updated 10/31/2005
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