Opioid pretreatment alters blood-brain barrier penetration of doxorubicin in animal models: new strategy and application in glioblastoma care
Anna Lisa Iorio, email@example.com; Martina Da Ros, firstname.lastname@example.org; Maurizio Lucchesi, email@example.com ; Giancarlo la Marca, firstname.lastname@example.org; Laura Giunti, email@example.com; Alessia Stival, firstname.lastname@example.org ; Sabrina Becciani, email@example.com ; Maurizio de Martino, firstname.lastname@example.org ; Lorenzo Genitori, email@example.com; Iacopo Sardi, firstname.lastname@example.org
Doxorubicin (Dox) shows a reduced penetration through blood-brain barrier (BBB) mediated by P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP) efflux transporters, which can translate in a lack of efficacy in the treatment of glioblastoma. Recently, we have attempted to improve the therapeutic efficacy of pharmacological treatment in malignant brain tumors by safe and temporary BBB permeabilization. We have demonstrated that morphine and, to a lower level, ondansetron and dexamethasone allow an accumulation of doxorubicin within the rat brain by LC-MS/MS mass spectrometry. All these drugs are substrates of P-gp and BCRP efflux pumps. The aim of our study was to expand our preliminary observation, to understand the mechanism of action of BBB “permeabilization” induced by morphine or other drugs, and to evaluate this method in the animal model.
We have developed the following points:
i) Quantifying the drug levels that don’t usually cross the BBB after morphine pre-treatment in a preclinical model. Verifying the cytotoxic effect of morphine plus doxorubicin (and other chemotherapeutic agents) by using MTT and TUNEL analysis in glioblastoma cell lines.
ii) Quantifying the drug levels that don’t usually cross the BBB after morphine pre-treatment in an artificial BBB through a monolayer of MDCKII cells over-expressing the human P-gp or BCRP.
Our preliminary results suggested that blocking efflux transporters by pretreatment with morphine, ondansetron or dexamethasone have allowed doxorubicin penetration inside the brain, without acute cardiac or renal toxicity. These preliminary results enable novel therapeutic approaches against glioblastoma, with molecules that are usually stopped by the BBB.