Shifting the paradigm of PSMA delivery in prostate cancer for internal radiotherapy: An innovative ultrasound-mediated approach

Radioligand therapy targeting prostate-specific membrane antigen (PSMA) has demonstrated promising clinical outcomes for patients with metastatic castration-resistant prostate cancer. However, accumulation in non-target organs can lead to significant radiotoxicity, affecting patient well-being and potentially requiring treatment discontinuation. Ultrasound combined with microbubbles (USMB) has been shown to transiently permeabilize biological barriers, enabling efficient and safe drug delivery to tumor tissues while minimizing dose-limiting toxicities. This study explores the impact of different conditions of USMB on the distribution of the diagnostic radiopharmaceutical [¹⁸F]F-PSMA-1007 as a preliminary step before applying therapeutic radiopharmaceuticals (RPs) in a preclinical subcutaneous model. Immunodeficient mice bearing human LNCaP tumors were treated with different ultrasound parameters (i.e., pulse length and pressure). Each mouse received an intravenous injection of [¹⁸F]F-PSMA-1007 (5.1 ± 1.7 MBq) and was imaged by PET/CT 2 h post-injection (p.i.). Additionally, an intravenous injection of TRITC Dextran (100 µL, 70 kDa, 5 mg/mL) was administered to quantify its extravasation into the tumor, correlated with PSMA and CD31 expression via immunofluorescence. Contrast-enhanced ultrasound imaging was also performed to assess tumor perfusion. Results showed a mild, though non-significant, trend toward increased [18 F]F-PSMA-1007 in most groups compared to the control, except for those exposed to short pulses associated with high-pressure. These findings highlight the potential of USMB to enhance drug delivery for PSMA uptake but also underscore the necessity for careful consideration of ultrasound parameters to prevent tissue damage.