The blood-brain barrier is the primary obstacle to efficient intracerebral drug delivery. Focused ultrasound, in conjunction with microbubbles, is a targeted and non-invasive way to disrupt the blood-brain barrier. Many commercially available ultrasound contrast agents and agents specifically designed for therapeutic purposes have been investigated in ultrasound-mediated blood-brain barrier opening studies. The new generation of sono-sensitive agents, such as liquid-core droplets, can also potentially disrupt the blood-brain barrier after their ultrasound-induced vaporization. In this review, we describe the different compositions of agents used for ultrasound-mediated blood-brain barrier opening in recent studies, and we discuss the challenges of the past five years related to the optimal formulation of agents.

Focused ultrasound in combination with microbubbles (FUS) provides an effective means to locally enhance the delivery of therapeutics to the brain. Translational and quantitative imaging techniques are needed to noninvasively monitor and optimize the impact of FUS on blood–brain barrier (BBB) permeability in vivo. Positron-emission tomography (PET) imaging using [18F]2-fluoro-2-deoxy-sorbitol ([18F]FDS) was evaluated as a small-molecule (paracellular) marker of blood–brain barrier (BBB) integrity. [18F]FDS was straightforwardly produced from chemical reduction of commercial [18F]2-deoxy-2-fluoro-D-glucose. [18F]FDS and the invasive BBB integrity marker Evan’s blue (EB) were i.v. injected in mice after an optimized FUS protocol designed to generate controlled hemispheric BBB disruption. Quantitative determination of the impact of FUS on the BBB permeability was determined using kinetic modeling. A 2.2 ± 0.5-fold higher PET signal (n = 5; p < 0.01) was obtained in the sonicated hemisphere and colocalized with EB staining observed post mortem. FUS significantly increased the blood-to-brain distribution of [18F]FDS by 2.4 ± 0.8-fold (VT; p < 0.01). Low variability (=10.1%) of VT values in the sonicated hemisphere suggests reproducibility of the estimation of BBB permeability and FUS method. [18F]FDS PET provides a readily available, sensitive and reproducible marker of BBB permeability to noninvasively monitor the extent of BBB disruption induced by FUS in vivo.

Gene therapy represents a powerful therapeutic tool to treat diseased tissues and provide a durable and effective correction. The central nervous system (CNS) is the target of many gene therapy protocols, but its high complexity makes it one of the most difficult organs to reach, in part due to the blood-brain barrier that protects it from external threats. Focused ultrasound (FUS) coupled with microbubbles appears as a technological breakthrough to deliver therapeutic agents into the CNS. While most studies focus on a specific targeted area of the brain, the present work proposes to permeabilize the entire brain for gene therapy in several pathologies. Our results show that, after i.v. administration and FUS sonication in a raster scan manner, a self-complementary AAV9-CMV-GFP vector strongly and safely infected the whole brain of mice. An increase in vector DNA (19.8 times), GFP mRNA (16.4 times), and GFP protein levels (17.4 times) was measured in whole brain extracts of FUS-treated GFP injected mice compared to non-FUS GFP injected mice. In addition to this increase in GFP levels, on average, a 7.3-fold increase of infected cells in the cortex, hippocampus, and striatum was observed. No side effects were detected in the brain of treated mice. The combining of FUS and AAV-based gene delivery represents a significant improvement in the treatment of neurological genetic diseases.

No abstract

Passive cavitation detection can be performed to monitor microbubble activity during brain therapy. Microbubbles under ultrasound exposure generate a response characterized by multiple nonlinear emissions. Here, the wide bandwidth of capacitive micromachined ultrasonic transducers (CMUTs) was exploited to monitor the microbubble signature through a rat skull and a macaque skull. The intrinsic nonlinearity of the CMUTs was characterized in receive mode. Indeed, undesirable nonlinear components generated by the CMUTs must be minimized as they can mask the microbubble harmonic response. The microbubble signature at harmonic and ultra-harmonic components (0.5-6 MHz) was successfully extracted through a rat skull using moderate bias voltage.

No abstract

Purpose The non-transported and non-metabolized sorbitol derivative [18F]2-fluoro-2-deoxy-sorbitol ([18F]FDS) can be straightforwardly obtained from chemical reduction of commercial [18F]2-deoxy-2-fluoro-D-glucose. [18F]FDS was evaluated as a small-molecule (paracellular) marker of blood-brain barrier (BBB) integrity for PET. Methods Five mice underwent focused ultrasound (FUS) to generate spatially controlled BBB disruption in the right hemisphere. PET kinetics of [18F]FDS in each brain hemisphere were described by a 1-tissue compartment model using an image-derived input function. Results BBB disruption resulted in a 2.4±0.8-fold increase in the brain distribution (VT, p<0.01) of [18F]FDS. Enhanced brain uptake was associated with an increase in the influx transfer rate K1 (+1.4±0.7-fold, p<0.05) and a decrease in the efflux transfer rate k2 (-1.7±0.4-fold, p<0.01). Conclusion Thanks to the quantitative performance of PET compared with other neuroimaging techniques, [18F]FDS PET and kinetic modelling provides a readily available and sensitive method for non-invasive determination of different levels of BBB permeability in vivo.

No abstract