Biotin-Functionalized Iridium-Based Nanoparticles as Tumor Targeted Photosensitizers for Enhanced Oxidative Damage in Tumor Photodynamic Therapy

The clinical application of photodynamic therapy (PDT) is hampered by the suboptimal tumor-targeting properties of photosensitizers (PSs) and the presence of abundant antioxidants in cancer cells. To overcome these limitations, in this study, we proposed a formulation of an Ir(III) complex into a promising tumor-targeted coordination polymer (Ir-PB), which could self-assemble into nanoparticles (Ir-PB NPs) for bioimaging and tumor-targeted PDT. Ir-PB NPs were found to efficiently target A549 cells and specifically accumulate in the mitochondria. Under light irradiation (400 nm, 10 mW/cm 2, 15 min), Ir-PB NPs could trigger cell death through a combination of apoptosis and ferroptosis pathways by the photoinduced depletion of nicotinamide adenine dinucleotide phosphate (NADPH) and glutathione (GSH) and the photoinduced production of single oxygen ( 1 O 2 ). The mechanisms featured the attenuation of the antioxidant capacity of tumor cells, the reduction of mitochondrial membrane potential (MMP), decrease in ATP production, activation of Caspase-3 protein, accumulation of lipid peroxidation (LPO), shrinkage of mitochondria, and down-regulation of glutathione peroxidase 4 (GPX4). The effectiveness of Ir-PB NPs in inhibiting tumor growth upon light irradiation was confirmed using an A549 xenograft mouse model. This study presents a promising strategy for developing photodynamic drugs that have excellent tumor-targeting abilities and enhance the efficiency of PDT.