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Adenosine 5'-triphosphate-sensitive Potassium Channel-mediated Blood-Brain Tumor Barrier Permeability Increase in a Rat Brain Tumor Model

Maxine Dunitz Neurosurgical Institute and Burns and Allen Research Institute, Cedars-Sinai Medical Center, Los Angeles, California

Brain tumor microvessels/capillaries limit drug delivery to tumors by forming a blood-brain tumor barrier (BTB). The BTB overexpresses ATP-sensitive potassium (K_ATP) channels that are barely detectable in normal brain capillaries, and which were targeted for BTB permeability modulation. In a rat brain tumor model, we infused minoxidil sulfate (MS), a selective K_ATP channel activator, to obtain sustained, enhanced, and selective drug delivery, including various sized molecules, across the BTB to brain tumors. Glibenclamide, a selective K_ATP channel inhibitor, significantly attenuated the MS-induced BTB permeability increase. Immunocytochemistry and glibenclamide binding studies showed increased K_ATP channel density distribution on tumor cells and tumor capillary endothelium, which was confirmed by K_ATP channel potentiometric assay in tumor cells and brain endothelial cells cocultured with brain tumor cells. MS infusion in rats with brain tumors significantly increased transport vesicle density in tumor capillary endothelial and tumor cells. MS facilitated increased delivery of macromolecules, including Her-2 antibody, adenoviral-green fluorescent protein, and carboplatin, to brain tumors, with carboplatin significantly increasing survival in brain tumor-bearing rats. K_ATP channel-mediated BTB permeability increase was also demonstrated in a human, brain tumor xenograft model. We conclude that K_ATP channels are a potential target for biochemical modulation of BTB permeability to increase antineoplastic drug delivery selectively to brain tumors.

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