Photothermal nanozymes to self-augment combination cancer therapy by dual-glutathione depletion and hyperthermia/acidity-activated hydroxyl radical generation

Abstract

Chemodynamic therapy (CDT) has emerged as a promising strategy for tumor treatment. Nevertheless, the low Fenton catalytic efficiency and the high concentration of glutathione (GSH) in cancer cells largely decline antitumor efficacy of CDT. To self-augment antitumor effect of the CDT by combining with photothermal therapy (PTT), the unique photothermal nanozymes that doubly depleted GSH, and generated massive hydroxyl radicals (·OH) in the hyperthermia/acidity-activated manner were developed. Through the coordination of Fe³⁺ ions with PEGylated chitosan (PEG-CS)-modified polydopamine (PDA) nanoparticles, the attained Fe³⁺@PEG-CS/PDA nanozymes showed outstanding colloidal stability, photothermal conversion efficiency and acidity-triggered Fe³⁺ release. By GSH-mediated valence states transition of Fe³⁺ ions and Michael reaction between GSH and quinone-rich PDA, the nanozymes sufficiently executed dual depletion of GSH with the elevated temperature.Under mimic tumor acidity and near-infrared (NIR) irradiation condition, the endocytosed nanozymes effectively converted intracellular H₂O₂ into toxic ·OH upon amplified Fenton reaction, thereby potently killing 4T1 cancer cells and RAW 264.7 cells. Importantly, the nanozymes prominently suppressed 4T1 tumor growth in vivo and metastasis of cancer cells by CDT/PTT combination therapy without significant systemic toxicity. Our study provides novel visions in design of therapeutic nanozymes with great clinical translational prospect for tumor treatment.

Keywords: Chemodynamic/photothermal therapy; Dual-GSH depletion; Hyperthermia/acidity-activated Fenton reaction; Nanozymes; Polydopamine.