Mechanism, monitoring, and drug delivery of the ultrasound-induced blood-brain barrier opening

Abstract

Worldwide, neurodegenerative diseases account for more than 20 million patients. Aging greatly increases the risk of neurodegenerative disease while the average age of Americans is steadily increasing. Numerous small- and large-molecule drugs have been developed for treatment of neurodegenerative diseases but with mixed success. This is mainly because, when administered systemically in vivo, the blood-brain barrier (BBB) inhibits their delivery to the regions affected. Safe and localized opening of the BBB has been proven to present a significant challenge. Focused ultrasound (FUS) in conjunction with microbubbles remains the sole technique that can induce localized BBB opening noninvasively, selectively, and transiently. Over the past few years, our group has been able to unveil several aspects of the technology in order to (a) unveil the physical mechanism of opening, (b) maintain safety, (c) establish a non-MRI type of monitoring technique, (d) control the volume and permeability of opening through the microbubble used, (e) demonstrate large animal feasibility, and (f) determine the range of molecular sizes delivered. We have also shown that neurotrophic agents are capable of triggering downstream effects into the neuronal nucleus through the induced opening. All the aforementioned aspects including initial drug efficacy findings in large animals will be discussed.