Enhancement in blood-tumor barrier permeability and delivery of liposomal doxorubicin using focused ultrasound and microbubbles: evaluation during tumor progression in a rat glioma model

Effective drug delivery to brain tumors is often challenging because of the heterogeneous permeability of the ?blood tumor barrier? (BTB) along with other factors such as increased interstitial pressure and drug efflux pumps. Focused ultrasound (FUS) combined with microbubblescan enhance the permeability of the BTB in brain tumors, as well as the blood?brain barrier in the surrounding tissue. In this study, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was used to characterize the FUS-induced permeability changes of the BTB in a rat glioma model at different times after implantation. 9L gliosarcomacells were implanted in both hemispheres in male rats. At day 9, 14, or 17 days after implantation, FUS-induced BTB disruption using 690?kHz ultrasound and definity microbubbleswas performed in one tumor in each animal. Before FUS, liposomal doxorubicin was administered at a dose of 5.67?mg?kg?1. This chemotherapy agent was previously shown to improve survival in animal glioma models. The transfer coefficient Ktrans describing extravasation of the MRI contrast agentGd-DTPA was measured via DCE-MRI before and after sonication. We found that tumor doxorubicin concentrations increased monotonically (823?????600, 1817?????732 and 2432?????448?ng?g?1) in the control tumors at 9, 14 and 17?d. With FUS-induced BTB disruption, the doxorubicin concentrations were enhanced significantly (P? drug carriers, as they suggest that even large/late-stage tumors can benefit from FUS-induced drug enhancement. Corresponding enhancements in Ktrans were found to be variable in large/late-stage tumors and not significantly different than controls, perhaps reflecting the size mismatch between the liposomal drug (~100?nm) and Gd-DTPA (molecular weight: 938 Da; hydrodynamic diameter: ?2?nm). It may be necessary to use a larger MRI contrast agentto effectively evaluate the sonication-induced enhanced permeabilization in large/late-stage tumors when a large drug carriersuch as a liposome is used.