Modulation of BBB to Enhance CNS Chemotherapy

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DESCRIPTION: (provided by Applicant) This application is a request for a Mentored Research Scientist Development Award (KO1) to further Dr. Natalie Eddington's research in the area of anticancer drug delivery and pharmacokinetics. Dr. Eddington's long term goal is to enhance drug delivery of anticancer agents to the brain by modulating factors inherent in blood brain barrier physiology that serve to hinder drug transport. The main focus of her research has been to elucidate underlying pharmacokinetic related factors of drug distribution that are important in drug delivery and disposition. To that end, the goals of her research program are to better understand mechanistic activity at the blood brain barrier (BBB) that limit drug transport and modulate these factors to enhance drug delivery. Two factors that minimize drug transport across the BBB are: (1) the multidrug resistant protein, P-glycoprotein, which effectively ejects drugs out of the brain at the BBB, and (2) the presence of tight junctions in the BBB, which minimizes paracellular transport of drugs into the brain via the BBB. Modulation of the blood brain barrier by reducing P-glycoprotein mediated drug efflux or by reversibly opening tight junctions should theoretically enhance drug delivery to the brain. This proposal seeks training to pursue two research projects: One project seeks to examine the ability of a series of compounds, the enaminones, in reversing the P-gp mediated efflux of doxorubicin. The second project examines the ability of Zonula Occludens Toxin, a protein which can reversibly open the tight junctions, in enhancing drug delivery of a series of anticancer agents to the brain. A Mentored Research Scientist Award will allow Dr. Eddington to expand her expertise in the area of anticancer drug delivery and pharmacokinetics by focusing on the underlying mechanisms involved in drug delivery to the brain. In order to gain expertise in the areas mentioned, she will be mentored by Drs. Peter Melera and Yanto Lunardi-Iskandar. The training experience will involve gaining experience in optimizing cell culture techniques, Western Blot Analysis with quantitation, transfection techniques of P-gp into various cell lines, confocal microscopy to examine transport at the cellular level, and the development of a rodent glial tumor model. Experience in these areas will enhance her research skills and capabilities and will allow her to contribute to research in the area of anticancer drug delivery and pharmacokinetics.