A Single High-Intensity Shock Wave Pulse With Microbubbles Opens the Blood-Brain Barrier in Rats

Abstract

Focused extracorporeal shockwave (FSW), one kind of focused high-intensity pulsed ultrasound, has been shown to induce blood-brain barrier (BBB) opening in targeted brain areas in rat animal models with minimal detrimental effects below threshold intensity levels or iterations. In the current study, we found that the thresholds could be further reduced by the addition of microbubbles (ultrasound contrast agents or UCA; SonoVue). FSW with 2 × 10 6 MBs/kg of UCA (20% of clinical dosage) at an intensity level of 0.1 (peak positive pressure 5.4 MPa; peak negative pressure −4.2 MPa; energy flux density 0.03 mJ/mm 2) resulting in a 100% BBB opening rate without detectable hemorrhage or apoptosis in the brain. Significantly reduced free radical production was found compared with 0.5 MHz focused ultrasound at a peak negative pressure of 0.44 MPa (1% duty cycle and 4 × 10 7 MBs/kg of UCA). FSW devices offer advantages of commercial availability and high safety, and thus may facilitate future research and applications of focal BBB opening for oncological and pharmacological purposes.

Immune Escape in Glioblastoma Multiforme and the Adaptation of Immunotherapies for Treatment

“…Although this approach is effective in opening the barrier to therapeutic antibodies ( 219 ), it suffers from producing bystander tissue distortion and damage in experimental animals ( 220 ). In an attempt to overcome this issue, the technique has been refined to improve specificity and reduce energy transfer through the use of injected microbubbles ( 221 , 222 ). In this case, lower frequency ultrasound is used to stimulate microbubble oscillation and cavitation, disrupting the endothelial wall through local shock wave production and permitting access of therapeutic agents to the brain.…”

Investigation of the Therapeutic Effect of Doxorubicin Combined With Focused Shockwave on Glioblastoma

“…A major contribution of our SW approach is that it not only achieves results that are similar or superior to those of currently used approaches, but it does so with markedly fewer and less serious side effects. Our previous studies have shown that there was almost no generation of ROS (including singlet oxygen, hydroxyl radical and superoxide) through SW treatment, and even if microbubbles were added to promote cavitation, ROS was not increased ( 23 ). On the contrary, ultrasound significantly increased ROS.…”

“…UCA could also be combined with SW for intracranial drug delivery. Our previous study demonstrated the addition of UCA could effectively reduce the threshold of BBB opening, decrease the necessary pulse number, and enhance opening efficiency ( 23 ). However, output pressure should be carefully reduced to avoid possible side effects due to enhance cavitation effect.…”

“…In addition, the combination of ultrasound and UCA has been demonstrated to increase the production of reactive oxygen species (ROS), and then apoptosis was induced through a caspase-mediated pathway (21,22). Intracranial hemorrhage also remains a risk under the treatment of focused ultrasound combined with UCAs due to its relatively higher pressure level, huge number of pulses, and much longer treatment duration (23)(24)(25).…”

Natural Antibodies: Protecting Role of IgM in Glioblastoma and Brain Tumours

“…In order to surpass this obstacle, microbubbles are introduced alongside with lowfrequency ultrasound, resulting in microbubble cavitation and oscillation, leading to disruption of BBB in the local vicinity. This approach is one of the most promising methods to deliver IgM-based nanobodies, but the studies lack the long-term consequences and the degree of penetration that can be achieved based on this method as the efflux transport mechanism remains active [157,160,161] (Fig. 4).…”