A PSMA-Targeted Up-conversion Nanoplatform for Deep-Tissue dual activation Photodynamic and Sonodynamic Therapy of Castration Resistant Prostate Cancer.

Abstract

Photodynamic therapy (PDT) for prostate cancer is limited by the shallow penetration of visible light into deep-seated tumors. In contrast, sonodynamic therapy (SDT) enables noninvasive deep-tissue activation using ultrasound, while near-infrared photodynamic therapy (NIR-PDT) enhances tissue penetration through up-conversion-mediated activation. Based on these advantages, we developed a prostate-specific membrane antigen (PSMA)-targeted nanotheranostic platform (UCNPs@mSiO2/HPPH@TCS) to compare NIR-PDT and SDT in vitro for penetration-enhanced and targeted prostate cancer therapy. The nanoformulation consists of NaYF4:Yb3+, Er3+ up-conversion nanoparticles coated with mesoporous silica for high loading of HPPH (Photochlor), which functions as both photosensitizer and sonosensitizer, and a PSMA-targeted chitosan shell for selective tumor targeting. Physicochemical characterization confirms a uniform core-shell structure ([~]63 nm). Tissue-mimicking depth studies demonstrate that SDT and NIR-PDT achieve greater penetration than conventional 665 nm PDT in thicker tissue layers. Intracellular reactive oxygen species (ROS) analysis shows that SDT generates higher total ROS levels, whereas NIR-PDT produces greater singlet oxygen generation. Three-dimensional spheroid models further validate efficacy, demonstrating rapid spheroid collapse via apoptosis, with SDT inducing earlier apoptosis and more uniform penetration than PDT. Collectively, the results suggest SDT provides superior overall therapeutic efficacy compared with NIR-PDT, highlighting the potential of this nanoplatform for precision prostate cancer therapy.