This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.The blood-brain barrier (BBB) effectively prevents microtubule stabilizing drugs from readily entering the central nervous system (CNS). A major limiting factor for these stabilizing drugs and anticancer agents permeation across the BBB is the active efflux back into the circulation by the overexpression P-glycoprotein (P-gp). This study focuses on strategies to overcome P-gp mediated efflux of new taxane analogues, and other microtubule (MT) stabilizing agents that could be used to treat brain tumors and potentially, neurodegenerative diseases such as Alzheimer's disease. 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, we hypothesize 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 previous studies demonstrate the feasibility of making small chemical modifications to taxol to generate new analogues with reduced affinity for P-gp but retention of pharmacological activity. Upon successfully demonstrating that our hypothesis works, we plan to then apply this same method of generating new analogues to other anticancer agents or drugs with poor brain bioavailibility.
The specific aims of this project will be:1. Establish the primary cell culture of system of Bovine brain microvessel endothelial cells (BMECs) for high-throughput screening of anticancer drugs.2. To characterize active, functional transporter systems (i.e., MCT, OAT, and NaDC) present in the brain that may be utilized as alternative pathways of delivery of therapeutic agents.3. To determine the mechanistic pathway of a new taxane analogue synthesized by chemical modification by assessing the transcellular permeability properties.4. To determine uptake and permeability properties of other novel anticancer drugs in the brain to assess whether chemical modifications will enhance their brain availability.
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