Advances in targeted chemotherapy using MRI-guided focused ultrasound to disrupt the blood-brain barrier

Abstract

The clinical application of chemotherapy to brain malignancies has been severely limited because many potential therapeutic agents are typically unable to penetrate the blood-brain barrier (BBB). A novel approach to overcome this barrier uses focused ultrasound to induce localized BBB disruption in a targeted region of the brain and magnetic resonance imaging (MRI) to guide and monitor the procedure. The purpose of this thesis was to develop a technique using MRI-guided focused ultrasound for trans bbb drug delivery applications. This thesis demonstrates that MRI-guided focused ultrasound can be used to achieve consistent and reproducible BBB disruption without invasive craniotomy in rats, to enable doxorubicin to accumulate in normal brain at clinically therapeutic levels, and to increase the antitumoral efficacy of doxorubicin in a rodent model of aggressive glioma. Using a microbubble-based ultrasonographic contrast agent, focal BBB opening was consistently achieved using transcranial focal pressures of 1.2 MPa or greater; locations in the posterior brain exhibited consistent BBB disruption with applied focal pressures of 0.8 MPa or greater. When combined with systemic administration of liposomal doxorubicin, we achieved local drug concentrations of 900 ± 300 ng/g tissue in the brain with minimal tissue effects, and up to 5400 ± 700 ng/g tissue with more significant tissue damage, while accumulation in non-targeted contralateral brain tissue remained significantly lower (p < 0.001). In addition, MRI signal enhancement in the sonicated region correlated strongly with doxorubicin concentration in tissue (r = 0.87), suggesting that contrast-enhanced MRI may provide useful feedback on drug penetration.

(cont.) Finally, glioma-bearing rats treated with ultrasound-enhanced chemotherapy exhibited significantly longer median survival times (31 versus 25 days; p = 0.0007) and slower tumor growth (average tumor volume doubling time, 3.7 ± 0.5 days, versus 2.3 ± 0.3 days) than nontreated rats; rats which received standard intravenous chemotherapy showed no significant difference in survival or tumor growth rate. In sum, this thesis research provides pre-clinical data toward the development of MRI-guided focused ultrasound as a noninvasive method for the delivery of agents such as doxorubicin across the BBB to treat patients with diseases of the central nervous system.