An AIE-active type I photosensitizer based on N,N′-diphenyl-dihydrophenazine for high-performance photodynamic therapy under hypoxia

Abstract

Type I photodynamic therapy (PDT) has been demonstrated to be superior to type II PDT due to its better hypoxia tolerance. Nowadays, photosensitizers (PSs) featuring type I active free radicals (O₂⁻˙, ˙OH) and aggregation-induced emission (AIE) properties have received widespread attention, whose design strategies follow two aspects of the introduction of reductive strong electron donors (D) and acceptors (A) to enhance the ICT intensity and introducing heavy atoms. Hence, we designed and synthesized three D–A structure cyanine dyes DPpy, DMPpy, and DMPSI based on N,N′-diphenyl-dihydrophenazine (DHP) and its ortho-dimethyl-substituted derivative DMP. Among the three dyes, DMPpy, based on DMP linking with styrylpyridinium iodide, exhibited AIE properties, excellent type I ROS (O₂⁻˙, ˙OH) generation, and mitochondrial targeting ability with near-infrared (NIR) emission (∼700 nm) and large Stokes shifts (∼270 nm). Cell experiments demonstrated that DMPpy could effectively generate O₂⁻˙, which could inhibit the growth of cancer cells under normoxia (21% O₂) or hypoxia (8% and 1% O₂). This study developed new AIE-active PSs based on the DMP moiety, facilitating the advancement of type I photosensitizers for conquering the hypoxic dilemma of malignant tumors.