Targeted drug delivery in the brain via ultrasound-induced blood-brain barrier disruption

Abstract

The major challenge to using therapeutic agents in the brain is the blood-brain barrier (BBB), a composite of endothelial structures that exclude over 98% of small-molecule drugs and almost 100% of large-molecule neurotherapeutics from being transmitted into the brain. Currently available approaches to circumvent the barrier are invasive, nontargeted, or require huge expense of developing complex new drug systems. We have developed a method where the BBB is temporarily disrupted in the focal zone of a focused ultrasound transducer using low-power ultrasound bursts combined with an injection of an ultrasound contrast agent that consists of preformed microbubbles. By systematically focusing at multiple overlapping locations, one could prescribe the region in which the BBB is disrupted to conform to a desired target volume, permitting the delivery of therapeutic agents and reducing drug penetration to the rest of the brain. Ultrasound parameters that appear to be optimal for this procedure are compatible with transcranial focused ultrasound exposures. Our previous investigation of this technique has shown that the BBB disruption can be achieved without any additional unwanted effects to the brain tissue. The exposures appear to activate both passive transport of agents through the tight junctions as well as active vesicular transport across the endothelial cells.