Cellular trouble for cavitation dose monitoring in microbubble-mediated drug delivery?

Ultrasound-activated microbubbles have shown great drug delivery potential to treat cardiovascular disease and cancer, both preclinically and clinically [Bouakaz and Escoffre, Adv. Drug Deliver. Rev. 206, 115199 (2024)]. Drug delivery is induced through the mechanical forces that ultrasound-activated microbubbles exert onto tissue, which opens up drug delivery barriers. Although the mechanism remains unclear, it is clear that microbubbles need to oscillate above a threshold (0.9 μm oscillation amplitude for non-targetedmicrobubbles) to induce bioeffects. Bioeffects include cell membrane pore formation (i.e., sonoporation), which facilitates intracellular drug delivery, and opening of cell–cell contacts, which facilitates transendothelial drug delivery. Interestingly, we found no clear distinguishment in microbubble behavior that predicts the occurrence of sonoporation only or sonoporation plus cell–cell contact opening. However, the cytoskeleton F-actin organization within cells was found crucial for opening cell–cell contacts by oscillating microbubbles [Meijlink et al., J. Control. Release. 376, 1176–1189 (2024)]. At the same time, higher peak negative acoustic pressures were needed to induce transendothelial drug delivery than sonoporation in a microvessel-on-chip model, both for 10 and 1000 cycles of ultrasound (2 MHz) [Meijlink et al., Small 2407550 (2024)]. Taken together, our findings suggest that dose monitoring is feasible, which may be complicated by the cellular landscape.