Focused ultrasound–mediated noninvasive blood-brain barrier modulation: preclinical examination of efficacy and safety in various sonication parameters

Abstract

<jats:sec><jats:title>OBJECTIVE</jats:title><jats:p>The application of pharmacological therapeutics in neurological disorders is limited by the ability of these agents to penetrate the blood-brain barrier (BBB). Focused ultrasound (FUS) has recently gained attention for its potential application as a method for locally opening the BBB and thereby facilitating drug delivery into the brain parenchyma. However, this method still requires optimization to maximize its safety and efficacy for clinical use. In the present study, the authors examined several sonication parameters of FUS influencing BBB opening in small animals.</jats:p></jats:sec><jats:sec><jats:title>METHODS</jats:title><jats:p>Changes in BBB permeability were observed during transcranial sonication using low-intensity FUS in 20 adult male Sprague-Dawley rats. The authors examined the effects of FUS sonication with different sonication parameters, varying acoustic pressure, center frequency, burst duration, microbubble (MB) type, MB dose, pulse repetition frequency (PRF), and total exposure time. The focal region of BBB opening was identified by Evans blue dye. Additionally, H &amp; E staining was used to identify blood vessel damage.</jats:p></jats:sec><jats:sec><jats:title>RESULTS</jats:title><jats:p>Acoustic pressure amplitude and burst duration were closely associated with enhancement of BBB opening efficiency, but these parameters were also highly correlated with tissue damage in the sonicated region. In contrast, MB types, MB dose, total exposure time, and PRF had an influence on BBB opening without conspicuous tissue damage after FUS sonication.</jats:p></jats:sec><jats:sec><jats:title>CONCLUSIONS</jats:title><jats:p>The study aimed to identify these influential conditions and provide safety and efficacy values for further studies. Future work based on the current results is anticipated to facilitate the implementation of FUS sonication for drug delivery in various CNS disease states in the near future.</jats:p></jats:sec>

Temporary blood–brain barrier disruption by low intensity pulsed ultrasound increases carboplatin delivery and efficacy in preclinical models of glioblastoma

“…Ultrasound parameters used in this mouse model (1-MHz, 0.3 MPa peak pressure, 25-ms pulses at 1 Hz, 200µl SonoVue/animal) were similar to those reported in other murine studies [22]. BBB opening evaluated by Evans's blue and the safety profile assessed by histology were similar to those reported in larger animal models [8,14].…”

Efficient Blood-Brain Barrier Opening in Primates with Neuronavigation-Guided Ultrasound and Real-Time Acoustic Mapping

“…Our system is thus suitable for both preclinical and clinical applications based on the non-thermal (mechanical) effects that require iterative treatment such as BBB opening, drug delivery, and neuromodulation. On the other hand, the safety is considered to be mainly dependent upon the acoustic parameters and dosage of microbubbles used 36 , 37 , and less affected by the system used.…”

Recent Strategies for Targeted Brain Drug Delivery

“…On the other hand, microbubbles with targeting ability are also being studied to increase their accumulation in target regions. For glioma targeting, vascular endothelial growth factor (VEGF) receptor-2 mAb-conjugated microbubbles 79) or folateconjugated microbubbles 80) have been developed. These ultrasound-responsive formulations may be utilized as diagnostic as well as therapeutic agents, referred to as "theranostics.…”