Work

Ultrasound-activated microbubbles mediate F-actin disruptions and endothelial gap formation during sonoporation

Year: 2024

Type: article

Abstract: Locally opening up the endothelial barrier in a safe and controlled way is beneficial for drug delivery into the extravascular tissue. Although ultrasound-induced microbubble oscillations can affect the endothelial barrier integrity, the mechanism remains unknown. Here we uncover a new role for F-actin in microbubble-mediated endothelial gap formation. Unique simultaneous high-resolution confocal microscopy and ultra-high-speed camera imaging (10 million frames per second) reveal that single oscillating microbubbles (radius 1.3-3.8 μm; n = 48) induce sonoporation in all cells in which F-actin remodeling occurred. F-actin disruption only mainly resulted in tunnel formation (75 %), while F-actin stress fiber severing and recoil mainly resulted in cell-cell contact opening within 15 s upon treatment (54 %) and tunnel formation (15 %). F-actin stress fiber severing occurred when the fibers were within reach of the microbubble's maximum radius during oscillation, requiring normal forces of ≥230 nN. In the absence of F-actin stress fibers, oscillating microbubbles induced F-actin remodeling but no cell-cell contact opening. Together, these findings reveal a novel mechanism of microbubble-mediated transendothelial drug delivery, which associates with the underlying cytoskeletal F-actin organization.

Source: Journal of Controlled Release

DOI: 10.1016/j.jconrel.2024.10.066

Authors: Bram Meijlink, H. Rhodé van der Kooij, Yuchen Wang, Hongchen Li, Stephan Huveneers, Klazina Kooiman