AR/PARP Dual-Targeting Bioactive Photosensitizer for Photo-Immunotherapy of Prostate Cancer.

Abstract

Prostate cancer poses a severe threat to men's health worldwide, and conventional therapeutic modalities are associated with various limitations. Photodynamic therapy (PDT) offers distinctive advantages such as minimal invasiveness, mild side effects and repeatable treatment. However, the therapeutic efficacy of PDT is limited by two critical factors: the single functional property of traditional photosensitizers and the pathological tumor microenvironment. Accordingly, molecular targeting photosensitizers have been developed to address these drawbacks. Notably, long-term administration of single-target agents entails a high risk of drug resistance. Accordingly, based on two key targets closely implicated in the DNA repair pathways of prostate cancer cells, the androgen receptor (AR), and poly(ADP-ribose) polymerase (PARP), we proposed an AR/PARP dual-targeting photosensitizer strategy and synthesized a quinoxalinone-based photosensitizer QTEO, which can simultaneously target AR and PARP and exert a synergistic effect with photodynamic activity to induce DNA damage in cancer cells. The resulting damaged DNA fragments can further activate the innate immune pathways of the organism through a coordinated cascade of reactions. This promising strategy concurrently overcomes the limited functionality of conventional photosensitizers, the potential drug resistance induced by single-target agents, and the complex pharmacokinetic issues associated with multidrug combination therapy, ultimately enabling molecular-targeting photo-immunotherapy for prostate cancer.