Ultrasound-mediated drug-free theranostics for treatment of prostate cancer.

Abstract

Lipid-shelled nanobubbles (NBs) can be visualized and activated using noninvasive ultrasound (US) stimulation, leading to significant bioeffects. Prior work demonstrates that active targeting of NBs to prostate-specific membrane antigen (PSMA) overexpressed in prostate cancer (PCa) results in enhanced cellular internalization and prolongs NB retention with persistent, cancer-cell specific acoustic activity. In this work, we hypothesized that tumor-accumulated PSMA-NBs combined with low frequency unfocused therapeutic US (TUS) will lead to selective damage and induce a specific therapeutic effect in PSMA-expressing tumors compared to PSMA-negative tumors. We observed that the internalized NBs and cellular compartments were disrupted after the PSMA-NB + TUS (targeted NB therapy or TNT) application, yet treated cells remained intact and viable. <i>In vivo</i>, PSMA-expressing tumors in mice receiving TNT treatment demonstrated a significantly greater extent of apoptosis (78.4 ± 9.3 %, p < 0.01) compared to controls. TNT treatment significantly inhibited the PSMA expressing tumor growth and increased median survival time by 103 %, p < 0.001). A significant reduction in tumor progression compared to untreated control was also seen in an orthotopic rabbit PCa model. Results demonstrate that cavitation of PSMA-NBs internalized via receptor-mediated endocytosis into target PCa cells using unfocused ultrasound results in significant, tumor-specific bioeffects. The effects, while not lethal to PSMA-expressing cancer cells <i>in vitro</i>, result in significant <i>in vivo</i> reduction in tumor progression in two models of PCa. While the mechanism of action of these effects is yet unclear, it is likely related to a locally-induced immune response, opening the door to future investigations in this area.