Cyclopentylmalononitrile dye as an efficient photosensitizer for combined photodynamic and water-dependent reversible photoacidity therapy

Photodynamic therapy (PDT) has been applied in the clinical treatment of various tumors. However, the high oxygen dependency of PDT still remains as the major obstacle which undermines its therapeutic efficacy, especially for hypoxic tumors. Recently, we reported a water-dependent reversible photoacidity (W-RPA) mechanism, which is oxygen-independent and has great potential for tumor treatment. Here we find that a previously studied cyclopentanone photosensitizer (B-PEG5) for PDT also has W-RPA characteristic. However, its absorption mainly occurs in blue-green region, limiting the depth of phototherapy. Based on the structure of B-PEG5, a cyclopentylmalononitrile dye (BN-PEG5) with enhanced absorption in red region is designed and synthesized. Under irradiation of a 635 nm laser, BN-PEG5 can not only produce ROS, but also generate H⁺. Owing to its binary properties of PDT and W-RPA therapy, BN-PEG5 shows strong phototoxicity to multiple tumor cell lines (4T1, HeLa and MDA-MB-231) either in normoxic condition (∼20% O₂) or extreme hypoxic condition (<0.5% O₂). Furthermore, the IC50 values of BN-PEG5 to these cells in hypoxia (1.39 μM–2.18 μM) are comparable with the data of commercial drug HpD in normoxia (1.80 μM–2.65 μM), which indicates the advantages of combined PDT and W-RPA therapy in hypoxic tumor treatment.