Even though the blood-
brain tumor barrier (BTB) is more permeable than the blood-brain barrier (BBB), the BTB still significantly restricts the delivery of anticancer drugs to
brain tumors.
Brain tumor capillaries that form the BTB, however, express certain unique
protein markers that are absent or barely detectable in normal brain capillaries. We were able to biochemically modulate one such
protein marker, the
calcium-dependent
potassium (K(Ca)) channel, by using a specific K(Ca) channel agonist,
NS-1619, to obtain sustained enhancement of selective
drug delivery, including molecules of varying sizes, to
tumors in rat syngeneic and xenograft
brain tumor models. Immunolocalization and potentiometric studies showed increased K(Ca) channel distribution on
tumor cells compared with normal cells, suggesting that
tumor cell-specific signals might induce overexpression of K(Ca) channels in capillary endothelial cells, leading to increased BTB permeability. We also demonstrated that the cellular mechanism for K(Ca) channel-mediated BTB permeability increase is due to accelerated formation of pinocytotic vesicles, which can transport therapeutic molecules across the BTB. This concept was investigated by using
NS-1619 to facilitate increased delivery of
carboplatin to
brain tumor leading to enhanced survival in rats with
brain tumors. Additionally, we showed that K(Ca) channel modulation resulted in enhanced permeability to macromolecules, including Her-2
monoclonal antibody and
green fluorescent protein-adenoviral vectors, in a human,
primary brain-tumor xenograft model. Therefore, K(Ca) channels are a potential, promising target for biochemical modulation of BTB permeability to increase
antineoplastic drug delivery selectively to
brain tumors.