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/cm2, 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 (1O2). 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.