Impact of Focused Ultrasound-enhanced Drug Delivery on Survival in Rats with Glioma

Abstract

Malignancies of the brain remain difficult to treat with chemotherapy because the selective permeability of the blood‐brain barrier (BBB) blocks many potent agents from reaching their target. Previous studies have illustrated the feasibility of drug and antibody delivery across the BBB using MRI‐guided focused ultrasound. In this study, we investigated the impact of focused ultrasound‐enhanced delivery of doxorubicin on survival in rats with aggressive glioma. Sprague‐Dawley rats were implanted with 9 L gliosarcoma cells in the brain. Eight days after implantation, each rat received one of the following: (1) no treatment (control), (2) a single treatment with microbubble‐enhanced MRI‐guided focused ultrasound (FUS only), (3) a single treatment with i.v. liposomal doxorubicin (DOX only), or (4) a single treatment with microbubble‐enhanced MRI‐guided focused ultrasound and concurrent i.v. injections of liposomal doxorubicin (FUS+DOX). The survival time from implantation to death or euthanasia was recorded. We observed a modest but significant increase in median survival time in rats treated with combined MRI‐guided focused ultrasound chemotherapy, compared to chemotherapy alone (p<0.001). There was no significant improvement in survival between those who received stand‐alone chemotherapy and those who did not receive any treatment (p>0.10). Our study demonstrates for the first time a therapeutic benefit achieved with ultrasound‐enhanced drug delivery across the blood‐brain barrier. This confirmation of efficacy in an in vivo tumor model indicates that targeted drug delivery using MRI‐guided focused ultrasound has the potential to have a major impact on the treatment of patients with brain tumors and other neurological disorders.