Fibroblast activation protein α activatable theranostic pro-photosensitizer for accurate tumor imaging and highly-specific photodynamic therapy

Abstract

The development of activatable photosensitizers (aPSs) responding to tumor-specific biomarkers for precision photodynamic therapy (PDT) is urgently required. Due to the unique proteolytic activity and highly restricted distribution of tumor-specific enzymes, enzyme activatable photosensitizers display superior selectivity. Methods: Herein, a series of novel Fibroblast Activation Protein (FAP) activatable theranostic pro-photosensitizers were designed by conjugating the different N-terminal blocked FAP-sensitive dipeptide substrates with a clinical PS, methylene blue (MB), through a self-immolative linker, which resulting in the annihilation of the photoactivity (fluorescence and phototoxicity). The best FAP-responsive pro-photosensitizer was screened out through hydrolytic efficiency and blood stability. Subsequently, a series of in vitro and in vivo experiments were carried out to investigate the FAP responsiveness and enhanced PDT efficacy. Results: The pro-photosensitizers could be effectively activated by tumor-specific FAP in the tumor sites. After response to FAP, the "uncaged" MB can recover its fluorescence and phototoxicity for tumor imaging and cytotoxic singlet oxygen ( 1 O2) generation, eventually achieving accurate imaging-guided PDT. Simultaneously, the generated azaquinone methide (AQM) could serve as a glutathione (GSH) scavenger to rapidly and irreversibly weaken intracellular antioxidant capacity, realizing synergistic oxidative stress amplification and enhanced PDT effect. Conclusion: This novel FAP activatable theranostic pro-photosensitizers allow for accurate tumor imaging and admirable PDT efficacy with minimal systemic side effects, offering great potential in clinical precision antitumor application.

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