Effect of Inertial Cavitation by Ultrasound Active Silica Nanoparticles on 2- and 3D Cellular Systems

Macromolecular transport in tumors is often limited by tumor and matrix structure. These limitations can be addressed using focused ultrasound to apply mechanical force, but previous examples have used therapeutic levels that can damage tissue and risk off-target side effects. Instead, an acoustically interacting particle could reduce the levels of ultrasound required to enact tumor structure changes. Here, we used phospholipid coated hydrophobically modified mesoporous silica nanoparticles (PL-HMSNs) as cavitation nuclei to significantly reduce the intensities necessary to generate effects on cells and their surrounding matrix. First, we designed particles that retained acoustic activity in biological media over 24 h. These particles were then shown to bind to 2D cultures in as little as 15 min. Next, these particles demonstrated ablation of 2D cultures upon HIFU insonation. In 3D cultures, however, significant drops in fibronectin and cadherin content were observed while overall spheroid morphology and cell viability remained intact. This reduction in extracellular matrix allowed for greater accumulation and transport of a targeted affibody-enzyme therapeutic. Together these results suggest the possibility of using these nanoscale cavitation nuclei to reduce HIFU intensities needed to change tumor structure to enhance therapeutic transport.