Abstract
Methods to improve drug delivery efficiency through blood-brain barrier disruption (BBBD) based on microbubbles and focused ultrasound (FUS) are continuously being studied. However, most studies are being conducted in preclinical trial environments using small animals. The use of the human skull shows differences between the clinical and preclinical trials. BBBD results from preclinical trials are difficult to represent in clinical trials because various distortions of ultrasound by the human skull are excluded in the former. Therefore, in our study, a clinical validation platform based on a preclinical trial environment, using a human skull fragment and a rat model, was developed to induce BBBD under conditions similar to clinical trials. For this, a human skull fragment was inserted between the rat head and a 250 kHz FUS transducer, and optimal ultrasound parameters for the free field (without human skull fragment) and human skull (with human skull fragment) were derived by 300 mVpp and 700 mVpp, respectively. BBBD was analyzed according to each case using magnetic resonance images, Evans blue dye, cavitation, and histology. Although it was confirmed using magnetic resonance images and Evans blue dye that a BBB opening was induced in each case, multiple BBB openings were observed in the brain tissues. This phenomenon was analyzed by numerical simulation, and it was confirmed to be due to standing waves owing to the small skull size of the rat model. The stable cavitation doses (SCDh and SCDu) in the human skull decreased by 13.6- and 5.3-fold, respectively, compared to those in the free field. Additionally, the inertial cavitation dose in the human skull decreased by 1.05-fold compared to that of the free field. For the histological analysis, although some extravasated red blood cells were observed in each case, it was evaluated as recoverable based on our previous study results. Therefore, our proposed platform can help deduct optimal ultrasound parameters and BBBD results for clinical trials in the preclinical trials with small animals because it considers variables relevant to the human skull.
Highlights
Following the injection of microbubbles into blood vessels, focused ultrasound (FUS) is sonicated at the targeted brain blood vessel, and the blood-brain barrier (BBB) is temporarily disrupted by the vibration of microbubbles, resulting in improved drug permeability [11,12]
FUS combined with mi-with microbubbles is considered a promising method to these treat diseases these diseases it can crobubbles is considered a promising method to treat becausebecause it can improve thethe efficacy of drug delivery to theto brain and target
BBB disruption (BBBD) was analyzed according to the existence of the human skull using the developed clinical validation platform
Summary
Various studies have been conducted to increase drug efficacy by penetrating the BBB for entry into the brain [4,5]. In these studies, BBB disruption (BBBD) with microbubbles and low-intensity focused ultrasound (FUS) has been employed as the safest method, as it is non-invasive and can be repeatedly carried out [6,7]. Following the injection of microbubbles into blood vessels, FUS is sonicated at the targeted brain blood vessel, and the BBB is temporarily disrupted by the vibration of microbubbles, resulting in improved drug permeability [11,12]. A few clinical trials have demonstrated that this method is safe and promising for the treatment of brain diseases [13,14]
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