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.
Highlights
Various Approach to Overcome Blood-Brain Barrier (BBB)Many drug molecules and therapeutics cannot naturally permeate the BBB into the brain parenchyma, presenting a serious challenge to treating brain disorders
Reviewed by: Ai-Ho Liao, National Taiwan University of Science and Technology, Taiwan Feng Wang, Xinxiang Medical University, China
It has been reported that ultrasound can temporarily suppress Pglycoprotein expression, the most dominant multi-drug resistant protein found in the Blood-Brain Barrier (BBB), for days even after BBB closure (Cho et al, 2016)
Summary
Many drug molecules and therapeutics cannot naturally permeate the BBB into the brain parenchyma, presenting a serious challenge to treating brain disorders. An opening of tight junctions between endothelial cell barriers provides paths by which molecules can diffuse passively into the brain parenchyma. In non-physical delivery, drug molecules and therapeutics are systemically delivered to the luminal side of the BBB. The design of such approaches must consider several hurdles including first pass clearance, blood instability, immune response, and off-target effects (Chen et al, 2010; Upadhyay, 2014; Duskey et al, 2017). Since the BBB blocks nearly 98% of drugs from accessing the CNS, the use of focused ultrasound raises a potential therapeutic delivery platform to the CNS (Pardridge, 2005). While nonphysical delivery methods use a different mechanism, which depends on cellular non-specific or receptor uptake, to overcome BBB, FUS holds abovementioned advantages and provides high flexibility in combing with various CNS treatment modalities (Hsu et al, 2013; Fan et al, 2016)
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