Doxorubicin concentration in brain remains high for one day after triolein emulsion infusion induced BBB opening

Abstract

Aim: The purpose of this study was to assess changes in doxorubicin concentration in rabbit brain with respect to time after BBB opening induced by triolein emulsion infusion via a carotid artery and the mechanism of BBB opening.Materials and Methods: Doxorubicin (2.4 mg/kg) was infused immediately after triolein emulsion (1%) into rabbit carotid arteries. Bilateral hemispheres were harvested 2, 4, 6 12 and 24 h later and doxorubicin concentrations were measured fluorometrically. Doxorubicin concentration ratios of ipsilateral versus contralateral hemispheres were calculated, and a TEM study was performed to investigate the mechanism responsible for the increased vascular permeability induced by triolein.Results: Doxorubicin concentrations were higher in ipsilateral hemispheres at all time points, and peaked at 2 h after treatment. Doxorubicin was still detected in ipsilateral hemispheres at 24 h after treatment. TEM showed tight junction opening by triolein emulsion with lanthanum tracer spillage into neural interstitium and transcytotic vesicles.Conclusion: Doxorubicin was delivered into neural interstitium because of the increased vascular permeability of the BBB induced by triolein emulsion. Doxorubicin concentrations in brain peaked within 2 h of triolein and doxorubicin administration and remained high for 24 h. The study shows increased vascular permeability induced by triolein emulsion may involve paracellular and transcellular pathways.