Experimental Study on Targeted Methotrexate Delivery to the Rabbit Brain via Magnetic Resonance Imaging-Guided Focused Ultrasound

Abstract

The purpose of this study was to investigate the effects of targeted and reversible disruption of the blood-brain barrier (BBB) by magnetic resonance imaging (MRI)-guided focused ultrasound (FUS) and delivery of methotrexate (MTX) to the rabbit brain. The brains of 20 rabbits were sonicated by MRI-guided FUS at different exposure times, and then Evans blue extravasation, contrast-enhanced MRI, and histologic examination were performed to determine the optimal exposure time for reversible BBB disruption with minimal damage. Five rabbits were sonicated at the optimal exposure time after MTX was injected intravenously (IV); the targeted locations were included in the sonicated group, and the nontargeted contralateral counterparts were included in the IV control group. Five other rabbits were not subjected to sonication and were administered internal carotid artery (ICA) injections of MTX; the specimens of the counterpart brain tissue were harvested as the ICA group. The MTX concentration in all of the specimens was determined by high-performance liquid chromatography. The MTX concentration in the sonicated group (mean +/- SD, 7.412 +/- 1.471 microg/g of tissue) was notably higher than that in both the IV control group (0.544 +/- 0.084 microg/g) and ICA group (1.984 +/- 0.65 microg/g; P <.01). Magnetic resonance imaging-guided FUS can disrupt the BBB reversibly and deliver IV administered MTX to targeted brain locations; it brings about a greater than 10-fold increase in the drug level and is much more effective (approximately 3.7-fold) than drug delivery through the ICA without sonication. This may facilitate the development of improved treatment methods for central nervous system disorders.