Au-PtNPs@Mn(3)O(4) Nanozymes Enhance the Antitumor Effect of Photodynamic Therapy and Radiotherapy in Cervical Cancer by Modulating Tumor Hypoxia.

Photodynamic therapy (PDT) and radiotherapy (RT) are clinical treatment strategies for solid tumors. However, the uncontrolled proliferation of cancer cells leading to a hypoxic tumor microenvironment significantly reduces the efficacy. This study aimed to construct Au-PtNPs@Mn(3)O(4) composite nanozymes for modulating tumor hypoxia and enhancing PDT and RT in cervical cancer. Au-PtNPs@Mn(3)O(4) nanozymes were synthesized through self-assembly and electron transfer, followed by characterization and enzyme activity detection. Then, the cytotoxicity and distribution of Au-PtNPs@Mn(3)O(4) nanozymes in vitro and in vivo were evaluated. After investigating the cellular uptake, the efficacy of Au-PtNPs@Mn(3)O(4) nanozymes in vitro under normoxic and hypoxic atmospheres and in vivo was studied. Au-PtNPs@Mn(3)O(4) nanozymes were designed with three different types of enzyme-like activities, including peroxidase (POD), superoxide dismutase (SOD), and catalase (CAT). Also, Au-PtNPs@Mn(3)O(4) has higher tumor-targeting efficiency without side effects. In vitro, Au-PtNPs@Mn(3)O(4) synergistic therapy with PDT and RT significantly attenuated the cell proliferation of HeLa cells but facilitated ROS level ((1)O(2) and (•)OH), cell apoptosis, and cell death under normoxic and hypoxic atmospheres. Also, Au-PtNPs@Mn(3)O(4) synergistic therapy with PDT and RT could disrupt the established redox homeostasis in tumors through a series of enzymatic cascade reactions. Moreover, Au-PtNPs@Mn(3)O(4) synergistic therapy with PDT and RT also repressed the growth in tumor xenografts in vivo while promoting ROS generation. The Au-PtNPs@Mn(3)O(4) nanozymes can improve the effect of PDT and RT by alleviating hypoxia in cervical cancer, thus achieving a multimodal synergistic therapy. This study presents a typical paradigm to harness hypoxic tumor microenvironments for highly effective cancer therapy.