The association of statins plus LDL receptor-targeted liposome-encapsulated doxorubicin increases the in vitro drug delivery across blood-brain barrier cells.

Background and purpose: The passage of drugs across the blood-brain barrier (BBB) limits the efficacy of chemotherapy in brain tumors. For instance the anticancer drug doxorubicin, that is effective against glioblastoma in vitro, has poor efficacy in vivo, because it is extruded by P-glycoprotein (Pgp/ABCB1), multidrug resistance-related proteins and breast cancer resistance protein (BCRP/ABCG2) of BBB cells. Aim of the study is to convert poorly permeant drugs like doxorubicin in drugs able to cross the BBB. Experimental approach: Experiments were performed on primary human cerebral microvascular endothelial hCMEC/D3, alone and co-cultured with human brain and epithelial tumor cells. Key results: We found that statins reduced the efflux activity of Pgp/ABCB1 and BCRP/ABCG2 in hCMEC/D3 cells by increasing the synthesis of nitric oxide that elicits the nitration of critical tyrosine residues on the transporters. Taking advantage from this event and from the statin-driven exposure of the low density lipoprotein (LDL) receptor on BBB cells, as well as on tumor cells like human glioblastoma, the association of statins plus drug-loaded nanoparticles engineered as LDLs was effective to vehicle a non permeant drug like doxorubicin across BBB, to allow its delivery into primary and metastatic brain tumor cells and to achieve significant anti-tumor cytotoxicity. Conclusions and Implications: We suggest that our "Trojan horse" approach, based on the administration of statins plus a LDL receptor-targeted liposomal drug, might have potential applications in the pharmacological therapy of different brain diseases for which BBB represents an obstacle.