Engineered Mesoporous Silica Nanoparticles Enhance Tumor Tissue Destruction and Modulate Tumor-Associated Macrophages at Reduced FUS Intensities

Abstract

Histotripsy has become an increasingly popular option for treating certain types of cancers because it is noninvasive and focused. However, current modalities for histotripsy treatment use large focused ultrasound (FUS) intensities to damage tissue, which can cause off-target effects such as burns and injury to nearby tissue. To improve upon this technology, we have developed engineered mesoporous silica nanoparticles that seed cavitating bubbles at ultrasound intensities 2–3 orders of magnitude lower than those used clinically (≥1000 W/cm2, time-averaged). When combined with resiquimod, a potent Toll-like receptor 7/8 agonist, macrophages grown in a tumor spheroid model adopted more of an antitumor phenotype than spheroids treated with FUS alone. In a breast cancer mouse model, tumor-associated macrophages treated with resiquimod, engineered mesoporous silica nanoparticles, and FUS dosed at 15.1 W/cm2, but not at 2.58 W/cm2, became more activated, and we observed greater tissue destruction in tumors compared to saline controls. These results demonstrate a novel, modified ultrasound treatment strategy for solid tumors by employing engineered mesoporous silica nanoparticles as cavitation seeding agents.