Large volume blood-brain barrier disruption by low frequency focused ultrasound: a method for targeted drug delivery and molecular imaging

The paper explores the feasibility of using low frequency image guided focused ultrasound as a noninvasive method to temporarily disrupt the blood-brain barrier (BBB) at targeted locations. This method could provide a means for targeted delivery of therapeutic or diagnostic agents to the brain. Brains of rabbits were targeted with 20 s burst sonications (10 ms, repetition frequency, 1 Hz.) using a focused ultrasound transducer (frequency, 260 kHz; diameter, 10 cm; radius of curvature, 8 cm) in a clinical magnetic resonance imaging (MRI) scanner. The peak rarefactional pressure amplitude during the burst was varied between 0.2 and 0.9 MPa. Each sonication was performed 10 s after an intravenous injection of an ultrasound contrast agent (Optison^®). The disruption of the BBB was evaluated by injecting MRI contrast agent (Magnevist^®). The animals were sacrificed at different times between 4 h and 5 weeks, after which histology or electron microscopy evaluation was performed. The results demonstrated that low frequency ultrasound bursts could induce local, reversible disruption of the BBB without undesired long-term effects. Electron microscopy showed that a large particle (horseradish peroxidase; molecular weight 40 kDa) could be delivered through the BBB disruption. This frequency is desirable since it can be focused through the intact skull without significant distortion of the ultrasound beam.