Focused Ultrasound-Mediated Blood-Brain Barrier Disruption for Enhanced Drug Delivery to Brain Tumors

Abstract

Transcranial focused ultrasound (FUS) in conjunction with intravenous circulating ultrasound contrast agents (UCAs) or microbubbles (MBs) can promote a transient and spatiotemporally selective increase in blood-brain barrier (BBB) permeability. The coupling of FUS with image guidance, such as magnetic resonance imaging (MRI)-guided FUS (MRgFUS), can further facilitate the visualization of targeted, localized therapeutic delivery to the central nervous system (CNS), potentially revolutionizing current treatment approaches for a spectrum of neurological diseases and conditions. Targeted and effective treatments of numerous CNS diseases are hindered by the BBB, a neurovascular structural and biological interface impeding the transport of molecules, particles, and cells between the systemic circulation and the underlying brain tissues. The functionality of FUS in conjunction with UCAs or MBs to safely and reversibly disrupt the BBB has become an area of intense research efforts both preclinically and clinically. Clinical efforts related to this approach are currently underway in patients with brain tumors, early Alzheimer’s disease, and amyotrophic lateral sclerosis (ALS). Critical ongoing issues include maintaining and monitoring safe levels of ultrasound exposure within different brain regions and tissues. Ongoing work related to real-time monitoring of the levels of acoustic energy deposition within brain regions warrants further investigation and integration into preclinical and clinical FUS systems. Despite the technological advancements in the field and the great promise of this new approach, there is a relative void in the knowledge pertaining to the underlying biological and molecular alterations induced by FUS in the brain. In this chapter, we review basic concepts of the BBB, the cellular and molecular composition of the BBB, the acoustic emissions and bio-effects associated with FUS-mediated activation of UCAs, and provide a summary of recent advances in strategies for detecting, controlling, and mapping FUS activity in the brain.