Plasmonic gold-titania-curcumin nanoantennas for synergistic quadruple photodynamic/mild photothermal/radiodynamic/chemotherapy of non-small cell lung cancer.

Lung cancer is known as a top cause of cancer-related mortality worldwide, and urgent attention is needed to enhance treatment efficacy with innovative therapeutic strategies. In this study, plasmonic nanoantennas of gold-titania-curcumin (PGTCNA) were synthesized, characterized, and applied as a photo/radiosensitizer for phototherapy and radiodynamic therapy (RDT) of A549 non-small cell lung cancer (NSCLC) in monolayer and tumorsphere models. PGTCNA contained gold and titania nanoparticles with diameters of 40 ± 8 nm and 29 ± 4 nm, respectively, along with curcumin. PGTCNA characterization showed that PGTCNA had a band gap of 2.4 eV, a zeta potential of +58.3 ± 4.9 mV, and a photothermal conversion efficiency of 50.7%, with the desired stability, hemocompatibility, and intrinsic capacity for reactive oxygen species (ROS) generation, particularly singlet oxygen (O). In the monolayer model, MTT cytotoxicity assays revealed that PGTCNA had IC values of 93 and 229 µg mL for cancerous (A549) and normal (MRC5) lung cells, respectively. In addition, laser light radiation following PGTCNA treatment resulted in disruption of mitochondrial membrane potential, photoporation, inhibition of cell migration, and alleviation of hypoxia-induced resistance in A549 cells. In both monolayer and tumorsphere models, treatment of A549 cells with PGTCNA in combination with 808-nm laser light and X-ray radiation (quadruple photodynamic/mild photothermal/radiodynamic/chemotherapy) synergistically reduced cell viability and enhanced ROS generation. In the tumorsphere model, the quadruple therapy triggered apoptosis in A549 tumorspheres. These findings suggested that PGTCNA acts as a promising photo/radiosensitizer to enhance the efficacy of photodynamic/mild photothermal/radiodynamic therapy of NSCLC, with the potential to overcome key challenges associated with radiotherapy.