Exploring Si-phthalocyanines with different valency for PSMA-targeted photodynamic therapy: Synthesis and preclinical validation.

Prostate cancer remains a significant health concern, with existing treatments often proving invasive or inadequate in preventing recurrence. This study explores the development and preclinical validation of silicon-phthalocyanine (SiPc)-based photosensitizers (PSs) targeted at prostate-specific membrane antigen (PSMA) for photodynamic therapy (PDT). Two PSMA-targeted SiPcs, monovalent and bivalent, were synthesized with axial conjugation through Si-O-C linkages to evaluate their efficacy and specificity. The bivalent SiPc-PQ-(PSMAi)2 demonstrated superior optical properties, reduced aggregation, and enhanced target specificity compared to the monovalent SiPc-PQ-PSMAi. Cellular and in vivo assays confirmed its high PSMA-specific uptake, potent photoinduced cytotoxicity mediated by reactive oxygen species, and significant tumor growth inhibition post-PDT. These findings underscore the potential of bivalent SiPc-PQ-(PSMAi)2 as an effective agent for targeted PDT, combining imaging and therapeutic capabilities for improved prostate cancer management. Further optimization and clinical evaluation could establish its role in theranostic strategies to enhance surgical outcomes and reduce recurrence.