Theranostics 2022; 12(8):3610-3627. doi:10.7150/thno.70308 This issue

Research Paper

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

Yong Luo1#, Zishan Zeng1#, Ting Shan1, Xiaoyu Xu1, Jie Chen1, Yuanfeng He1, Tao Zhang1, Zeqian Huang1, Guihong Chai1, Yanjuan Huang1, Yanfang Zhao2, Chunshun Zhao1✉

1. School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, P. R. China.
2. Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, P. R. China.
#These authors contribute equally to this work.

This is an open access article distributed under the terms of the Creative Commons Attribution License ( See for full terms and conditions.
Luo Y, Zeng Z, Shan T, Xu X, Chen J, He Y, Zhang T, Huang Z, Chai G, Huang Y, Zhao Y, Zhao C. Fibroblast activation protein α activatable theranostic pro-photosensitizer for accurate tumor imaging and highly-specific photodynamic therapy. Theranostics 2022; 12(8):3610-3627. doi:10.7150/thno.70308. Available from

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Graphic 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 α (FAPα) activatable theranostic pro-photosensitizers were designed by conjugating the different N-terminal blocked FAPα-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 FAPα-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 FAPα responsiveness and enhanced PDT efficacy.

Results: The pro-photosensitizers could be effectively activated by tumor-specific FAPα in the tumor sites. After response to FAPα, the “uncaged” MB can recover its fluorescence and phototoxicity for tumor imaging and cytotoxic singlet oxygen (1O2) 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 FAPα 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.

Keywords: Fibroblast activation protein α, activatable photosensitizer, oxidative stress amplification, tumor imaging, photodynamic therapy