Prostate specific membrane antigen-targeted multimodal imaging nanobubbles with ultrasound irradiation inhibit prostate cancer growth via autophagy activation

Ultrasound-targeted nanobubble destruction (UTND) is a promising noninvasive strategy for cancer treatment. However, off-target effects significantly influence UTND-mediated therapeutic efficacy and compromise accurate evaluation of tumors. Prostate-specific membrane antigen (PSMA) is overexpressed on the membranes of prostate cancer (PCa) cells, making it a key therapeutic target. In this study, we constructed theranostic-targeted nanobubbles (PSMA-617-ICG NBs) incorporating PSMA-617, a clinical small-molecule inhibitor of PSMA, and indocyanine green (ICG) employing mechanical vibration in conjunction with a biotin–avidin coupling strategy. PSMA-617-ICG NBs were selectively extravasated across the tumor vascular endothelium, bound to PSMA-positive cells and accumulated effectively within the tumor tissue. Under ultrasound irradiation, sufficient number of PSMA-617-ICG NBs adhered to the cell surface and generated close-range shock waves and cavitation, significantly destroying tumor cells and inhibiting PCa growth. Meanwhile, ultrasound, photoacoustic, and fluorescence imaging enabled monitoring of PSMA expression in tumor tissues, potentially providing imaging evidence to support UTND-mediated targeted therapy and assisting in tumor localization. Notably, mechanistic investigations revealed enhanced autophagosome formation and increased autophagosome–lysosome fusion in treated cells, indicating that UTND successfully activated autophagy and exerted an anti-tumor effect by inducing autophagy-related cell death. Therefore, this study demonstrates that the feasibility of using targeted multimodal imaging nanobubbles in combination with ultrasound irradiation as a potential therapeutic strategy for PCa. Statement of Significance This work presents prostate specific membrane antigen (PSMA)-targeted nanobubbles (PSMA-617-ICG NBs) that integrate multimodal imaging with ultrasound-triggered therapy for prostate cancer. Its significance lies in overcoming the off-target effects of conventional ultrasound targeted nanobubble destruction (UTND) through precise molecular targeting, and realizing ultrasound/photoacoustic/fluorescence imaging-guided therapy. Under ultrasound irradiation, the targeted nanobubbles successfully activate autophagy and exert an anti-tumor effect through inducing autophagy-related cell death. The targeted nanobubbles demonstrate specific accumulation in PSMA-positive tumors, monitoring therapy, and significantly amplified therapeutic efficacy against prostate cancer, bringing a non-invasive, promising approach for prostate cancer therapy.