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

Radiodynamic therapy (RDT), which produces 1O2 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 O2 by decomposing H2O2 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 H2O2 and catalyze the degradation of H2O2 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 1O2 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 H2O2 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.