Metabolizable Photosensitizers with Aggregation-Induced Emission for Photodynamic Cancer Therapy

Abstract

Photodynamic therapy (PDT) relies on photosensitizers to produce reactive oxygen species (ROS), particularly singlet oxygen (¹O₂), for tumor cell elimination. However, the slow metabolism of many photosensitizers in vivo often results in adverse effects. This study develops a metabolizable photosensitizer, 2-(4’-(10H-phenothiazin-10-yl)-[1,1’-biphenyl]-4-yl)-3-(4’-(1,2,2-triphenylvinyl)-[1,1’-biphenyl]-4-yl) fumaronitrile (TFP), with aggregation-induced emission (AIE) properties. TFP NPs, synthesized via a five-step process and formulated using DSPE-PEG2000, exhibited a maximum emission wavelength of 585 nm, an ¹O₂ yield of 28.5%, and selective oxidation by endogenous hypochlorite (ClO^–), which converts TFP into a nonemissive sulfoxide metabolite. This metabolic responsiveness, validated through HPLC and MS measurements in mouse plasma, ensures efficient clearance via hepatic cytochrome P450 enzymes, minimizing systemic toxicity. The in vitro study results indicated that the IC₅₀ values for TFP NPs against HeLa, H-22, and HepG2 cells were 21.8 μg/mL, 25.5 μg/mL, and 24.5 μg/mL, respectively, thereby confirming their efficacy across a range of cancer cell types. TFP NPs efficiently targeted HeLa cells in vitro, and in vivo studies in H22-tumor-bearing mice revealed a substantial reduction in tumor size with minimal side effects under 420 nm irradiation in a mouse model. These findings demonstrate that TFP NPs hold great potential as PDT agents, offering promising applications in cancer treatment with reduced systemic side effects compared to conventional agents.