Recently, Prof. Fude Feng (School of Chemistry and Chemical Engineering, Nanjing University) and Prof. Shu Wang (Key Laboratory of Organic Solids, Institute of Chemistry, Chinese Academy of Sciences) cooperated to develop a GSH and H2O2 co-activatable photosensitizer for photodynamic therapy against tumor cells. The results were published online at Angew. Chem. Int. Ed. (DOI: 10.1002/anie.202003895, VIP paper) under the title GSH and H2O2 Co-Activatable Mitochondria-Targeted Photodynamic Therapy under Normoxia and Hypoxia.
Design of activatable photosensitizers (aPSs) that are responsive to the tumor environments has attracted increasing research attentions. The strategy to utilize multiple endogenous stimuli for synergistic activation of photosensitizing process is promising for enhance the controllability and safety of photodynamic therapy (PDT). Based on the abnormal levels of the reduced glutathione (GSH) and peroxide hydrogen (H2O2) in the tumor cells, the present research established a GSH-H2O2 co-activatable and mitochondria targeted aPS. As shown in Figure 1, mitoaPS possesses a benzothiadiazole core with a nitro group in ortho to an alkylthiol substituent. After a series of free radical-participating reactions in the special redox environment containing GSH and H2O2, dual type 1 and type 2 photodynamic process is activated to generate excess reactive oxygen species identified as superoxide ions and singlet oxygen. The mitoaPS exhibited low dark cytotoxicity, but exerted strong PDT effect under normoxia and hypoxia conditions once activated, and also applicable by near infrared two-photon excitation.
Figure 1. (a) Proposed free radical-participating mechanism of NO2ArSH→NH2ArSO3H conversion mediated by GSH and H2O2. (b) Cartoon of the mitoaPS-based PDT. (b) Confocal images of mitoaPS-treated HeLa cells after 0−60 s of light irradiation.
In 2019, the previous study (Chem. Eur. J., 2019, 25, 9164−9169) on the thiyl radical-participating mechanism provided an important basis for this work. The mutually responsive probe (MRP) for the interplay of hydrogen sulfide (H2S) and H2O2 was developed, with extremely low background signal. The probe with mitochondria targeting capability was used to detect H2S and H2O2 in the special redox environment in the living cells, by coupling with a through bond energy transfer (TBET) process.
Figure 2. Detection of H2S−H2O2 based on a TBET mechanism
The first author is Jian Sun, a doctoral student of 2018, and Prof. Fude Feng and Prof. Shu Wang are co-corresponding authors. We thank Prof. Zijian Guo (School of Chemistry and Chemical Engineering, Nanjing University) and Prof. Jiajie Diao (University of Cincinnati College of Medicine, USA) for their helpful suggestions and discussions. We thank the National Basic Research Program of China (2015CB856300), National Key R&D Program of China (2017YFA0701301), Program for Changjiang Scholars and Innovative Research Team in University for financial support.