The Compression-Dominated Ultrasound Response of Poly(<i>n</i>-butyl cyanoacrylate) Hard-Shelled Microbubbles Induces Significant Sonoporation and Sonopermeation Effects <i>In Vitro</i>

The process of locally increasing the permeability of cell membranes or cell layers is referred to as sonoporation or sonopermeation, respectively, and opens up perspectives for drug delivery in cancer treatment by facilitating enhanced local drug accumulation. These effects are mediated by ultrasound-activated microbubbles in close proximity to cells. Here, the selection of ultrasound settings according to the intended effect on the biological tissue remains a challenge, especially for broadly size-distributed microbubbles, which show a heterogeneous response to ultrasound. For this purpose, we have analyzed the general response of narrower size-distributed poly(<i>n</i>-butyl cyanoacrylate) hard-shelled microbubbles to ultrasound via ultra-high-speed imaging and evaluated their ability to stimulate sonoporation and sonopermeation <i>in vitro</i> compared to lipid soft-shelled microbubbles. Ultra-high-speed imaging of hard-shelled microbubbles revealed either a compression-dominated or compression-only response at peak negative acoustic pressures higher than 165 kPa and an onset of bursting at 500 kPa. The <i>in vitro</i> experiments demonstrated that the hard-shelled microbubbles induced significant sonoporation and sonopermeation effects, also when only compressing at 300 kPa peak neagtive pressure. Compared to soft-shelled microbubbles, the effects were less prominent, which was attributed to differences in their ultrasound responses and size distributions. This <i>in vitro</i> validation of hard-shelled microbubbles qualifies them for future <i>in vivo</i> applications, which would benefit from their narrow size distribution, thereby allowing more control of their therapeutic effect by suitably adjusting the ultrasound parameters.