The drug delivery across blood brain barrier (BBB) is hampered by the presence of ATP binding cassette transporters, such as P-glycoprotein (Pgp), which effluxes back into the bloodstream several drugs, e.g. anticancer agents like doxorubicin. Pgp is induced by the transcription factor hypoxia-inducible factor-1α (HIF-1α). By using brain microvascular endothelial cells of murine and human origin cultured in normoxia and hypoxia, we observed that - despite species-specific differences, due to the differential basal activity of HIF-1α - the delivery of Pgp substrates is severely reduced in hypoxic BBB cells. Besides increasing the expression of Pgp, however, HIF-1α also increased the expression of low density lipoprotein receptor (LDLR), by activating the sterol regulatory element binding protein-2. The amount of LDLR was further enhanced by simvastatin in hypoxia. Combining simvastatin plus a “LDL-masked” liposomal doxorubicin is an effective strategy to improve the drug delivery across hypoxic BBB cells.
|Idioma original||Inglés estadounidense|
|Número de artículo||49|
|Número de páginas||12|
|Estado||Publicada - 2013|