title: Adenosine 5'-triphosphate-sensitive potassium channel-mediated blood-brain tumor barrier permeability increase in a rat brain tumor model.
abstract: 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.
authors.affiliation: Maxine Dunitz Neurosurgical Institute and Burns and Allen Research Institute, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA. ningarajn@cshs.org
authors.forename: Nagendra S
authors.initials: NS
authors.lastname: Ningaraj
authors.forename: Mamatha K
authors.initials: MK
authors.lastname: Rao
authors.forename: Keith L
authors.initials: KL
authors.lastname: Black
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism*; D001932:Brain Neoplasms / Q000098:blood supply* / Q000378:metabolism; D002463:Cell Membrane Permeability / Q000502:physiology; D004357:Drug Synergism; D004730:Endothelium, Vascular / Q000378:metabolism; D005260:Female; D005822:Genetic Vectors / Q000493:pharmacokinetics; D005910:Glioma / Q000098:blood supply* / Q000378:metabolism; D005905:Glyburide / Q000494:pharmacology; D049452:Green Fluorescent Proteins; D006801:Humans; D008164:Luminescent Proteins / Q000096:biosynthesis / Q000235:genetics; D008914:Minoxidil / Q000031:analogs & derivatives* / Q000494:pharmacology; D008969:Molecular Sequence Data; D026902:Potassium Channel Blockers / Q000493:pharmacokinetics / Q000494:pharmacology; D015221:Potassium Channels / Q000819:agonists / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000255:Adenosine Triphosphate; D000911:Antibodies, Monoclonal; D005905:Glyburide; D049452:Green Fluorescent Proteins; D008164:Luminescent Proteins; D008914:Minoxidil; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D018719:Erb-b2 Receptor Tyrosine Kinases; C039516:minoxidil sulfate ester