Erlotinib-conjugated iridium(III) complexes for EGFR-mediated photodynamic therapy of cancer.

Photodynamic therapy (PDT) offers superior spatiotemporal control compared with conventional cytotoxic cancer therapies through localized light activation. However, most photosensitizers rely on passive tumor accumulation and lack intrinsic mechanisms for active cancer cell targeting. Here, we report Ir_Erl, the first cyclometalated iridium (III) photosensitizer covalently conjugated to the EGFR inhibitor erlotinib through C10 alkyl linker. Ir_Erl retains the bright phosphorescence of the [Ir(pq)2(bpy)] core, enabling label-free imaging and intracellular tracking, while efficiently generating singlet oxygen through a strictly light-dependent type II reactive oxygen species (ROS) generation pathway. Ir_Erl preferentially accumulates in cancer cells relative to non-cancerous controls, and its uptake is markedly reduced by EGFR pre-blockage with gefitinib, indicating an EGFR-dependent accumulation mechanism. Upon white-light irradiation, Ir_Erl exerted potent photocytotoxicity (IC50 ~ 13 µM) while maintaining minimal dark toxicity (> 100 µM). In contrast, erlotinib alone displays no detectable phototoxicity under identical conditions. Collectively, these results demonstrate that Ir_Erl integrates receptor-directed delivery with efficient light-triggered ROS generation, establishing a modular strategy for the development of tumor-selective, light-activatable metal-complex photosensitizer.