Mitochondria-Targeted Nanosystem Enhances Radio–Radiodynamic–Chemodynamic Therapy on Triple Negative Breast Cancer

Radiodynamic therapy (RDT), which produces 1 O 2 and other reactive oxygen species (ROS) in response to X-rays, can be used in conjunction with radiation therapy (RT) to drastically lower X-ray dosage and reduce radio resistance associated with conventional radiation treatment. However, radiation–radiodynamic therapy (RT–RDT) is still impotent in a hypoxic environment in solid tumors due to its oxygen-dependent nature. Chemodynamic therapy (CDT) can generate reactive oxygen species and O 2 by decomposing H 2 O 2 in hypoxic cells and thus potentiate RT–RDT to achieve synergy. Herein, we developed a multifunctional nanosystem, AuCu-Ce6-TPP (ACCT), for RT–RDT–CDT. Ce6 photosensitizers were conjugated to AuCu nanoparticles via Au–S bonds to realize radiodynamic sensitization. Cu can be oxidized by H 2 O 2 and catalyze the degradation of H 2 O 2 to generate • OH through the Fenton-like reaction to realize CDT. Meanwhile, the degradation byproduct oxygen can alleviate hypoxia while Au can consume glutathione to increase the oxidative stress. We then attached mercaptoethyl-triphenylphosphonium (TPP-SH) to the nanosystem, targeting ACCT to mitochondria (colocalization Pearson coefficient 0.98) to directly disrupt mitochondrial membranes and more efficiently induce apoptosis. We confirmed that ACCT efficiently generates 1 O 2 and • OH upon X-ray irradiation, resulting in strong anticancer efficacy in both normoxic and hypoxic 4T1 cells. The down-regulation of hypoxia-inducible factor 1α expression and reduction of intracellular H 2 O 2 concentrations suggested that ACCT could significantly alleviate hypoxia in 4T1 cells. ACCT-enhanced RT–RDT–CDT can successfully shrink or remove tumors in radioresistant 4T1 tumor-bearing mice upon 4 Gy of X-ray irradiation. Our work thus presents a new strategy to treat radioresistant hypoxic tumors.