Photodynamic therapy (PDT) represents a promising therapeutic strategy for cancer management, yet developing highly efficient photosensitizers (PSs) remains a significant challenge. Herein, a series of novel carbazole/benzcdindolium PSs (3a–c) were designed and synthesized through incorporating a strong electron-accepting benzcdindolium group with the carbazole, and their photodynamic anticancer activities and associated mechanisms were evaluated. All compounds effectively induced the generation of reactive oxygen species (ROS), while compound 3a was chiefly associated with a type-I pathway, leading mainly to the formation of superoxide anions (O2•–) and hydroxyl radicals (•OH), effectively mitigating oxygen dependence in PDT. The increased generation of type-I ROS in 3a is attributed to its higher intersystem crossing rate constant (kISC) compared to 3b and 3c. 3a exhibited significant antiproliferative activity in both normoxic and hypoxic environments (IC50s,light = 1.8–6.3 μM), underscoring its low-oxygen-dependent chemo/photodynamic therapeutic potential. In vivo experiments showed that 3a significantly inhibited breast cancer tumor growth, achieving a 93.1% inhibition rate. Importantly, 3a triggered immunogenic cell death (ICD) in cancer cells by enhancing oxidative stress, promoting dendritic cell (DC) maturation, and boosting T cell infiltration. Consequently, novel carbazole/benzcdindolium PSs, as low-oxygen-dependent type-I PSs, may show promise for chemo/photodynamic/immune multitherapy and warrant further preclinical investigation.
Gong et al. (Tue,) studied this question.
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