Two photon-responsive gold nanocapsules enable targeted photothermal hyperthermia of chemoresistant melanoma: injection-route-dependent efficacy and renal evidence of fragment clearance

Abstract

Melanoma is a highly aggressive skin cancer that often develops resistance to chemotherapy, underscoring the need for new treatment strategies. Here we evaluate plasmonic gold nanocapsules (AuNCs) as photoresponsive agents for two-photon luminescence-assisted photothermal therapy in chemoresistant melanoma models. The performance of the AuNCs was assessed in two-dimensional cell cultures, three-dimensional paclitaxel-resistant B16-F10 melanoma spheroids, and a subcutaneous melanoma mouse model under near-infrared excitation. In vitro, AuNCs alone exhibited no cytotoxicity, but under 830 nm two-photon excitation, they produced strong two-photon luminescence and thermal effects that increased with nanocapsule concentration and laser power. This led to transient oxidative stress, apoptosis induction, and effective melanoma cell ablation under optimal conditions (80 μg mL-1 AuNCs, 12 mW laser power). In vivo, the route of nanoparticle administration proved decisive. A single 4-min 806 nm irradiation after intratumoral injection uniformly heated the lesion (≈45-50 °C), yielded durable tumour eradication, and sequestered >99% of detected gold in the necrotic scab, with only trace renal clearance. In contrast, the same laser fluence after peritumoral injection generated a superficial hot rim, spared the tumour core, allowing eventual regrowth, and left ∼65% of the injected gold systemically redistributed, mainly in the spleen and liver. These findings highlight the potential of AuNCs as potent, image-guided photothermal agents for chemoresistant melanoma, offering targeted tumor destruction with limited systemic exposure. They reveal the injection route is a critical determinant of both therapeutic success and nanoparticle biodistribution.