Theranostic Strategy of Focused Ultrasound Induced Blood-Brain Barrier Opening for CNS Disease Treatment

Abstract

Focused Ultrasound (FUS) in combination with gaseous microbubbles has emerged as a potential new means of effective drug delivery to the brain. Recent research has shown that, under burst-type energy exposure with the presence of microbubbles, this modality can transiently permeate the blood-brain barrier (BBB). The bioavailability of therapeutic agents is site-specifically augmented only in the zone where the FUS energy is targeted. The non-invasiveness of this approach makes FUS-induced BBB opening a novel and attractive means to perform localized CNS therapeutic agent delivery. Over the past decade, FUS-BBB opening has been preclinically confirmed to successfully enhance CNS penetration of therapeutic agents including chemotherapeutic agents, therapeutic peptides, monoclonal antibodies, and nanoparticles. Recently, a number of clinical human trials have begun to explore clinical utility. This review article, explores this technology through its physical mechanisms, summarizes the existing preclinical findings (including current medical device designs and technical approaches), and summarizes current ongoing clinical trials.

Keywords: Alzheimer's disease; blood-brain barrier; brain drug delivery; brain tumor; focused ultrasound.

Figure 1

BBB opening concepts: interaction of microbubbles and focused ultrasound transiently disrupts the tight junction of the capillary lumen to allow therapeutic agents to penetrate into the brain. The BBB return to normal a few hours following focused ultrasound exposure (Chai et al., 2014).

Figure 2

Modalities to identify BBB opening. Through ex-vivo examination, Evans blue dye can directly depict the BBB-opened region from gross section, or fluorescent dextran or the radioactivity readout through autoradiography from the brain gross section can be used to identify the BBB-opened region. Previous attempts have included in-vivo examination, ultrasonography via microbubble dynamic characterization, SPECT/ PET via radiotracer, contrast-enhanced MRI either via Gd-DTPA or MNPs), and dynamic contrast-enhanced MRI via Gd-DTPA (Lin et al., ; Liu et al., , , ; Chai et al., ; Fan et al., ; Xia et al., ; Wu et al., 2017).

Figure 3

Intraoperative monitoring and guidance of focused ultrasound-induced BBB opening. (A) Detection of subharmonic/ ultraharmonic of backscattered spectrum for real-time BBB opening monitoring (Tsai et al., 2016). (B) Dual transmit/receive mode ultrasound phase array to intraoperatively reconstruct focal beam for ultrasound energy guidance (Liu et al., 2018).