Cascade-Enhanced Catalytic Nanocomposite with Glutathione Depletion and Respiration Inhibition for Effective Starving-Chemodynamic Therapy Against Hypoxic Tumor

Abstract

Yiran Zhang,1– 4,* Hongzhi Hu,5,* Xiangtian Deng,6,* Qingcheng Song,2 Xin Xing,2,3 Weijian Liu,5 Yingze Zhang1– 3 1School of Medicine, Nankai University, Tianjin, 300071, People’s Republic of China; 2Department of Orthopaedic Surgery, Third Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050051, People’s Republic of China; 3NHC Key Laboratory of Intelligent Orthopaedic Equipment, Third Hospital of Hebei Medical University, Shijiazhuang, Hebei, People’s Republic of China; 4HeBei Ex&Invivo Biotechnology Co. Ltd, Shijiazhuang, Hebei, 050051, People’s Republic of China; 5Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People’s Republic of China; 6Orthopaedics Research Institute, Department of Orthopaedics, West China Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yingze Zhang; Weijian Liu, Email [email protected]; [email protected]: Although chemodynamic therapy (CDT) has attracted enormous attention in anti-tumor studies for converting endogenous hydrogen peroxide (H2O2) into toxic hydroxyl radicals (•OH) by Fenton-type reaction, the treating effects of using CDT alone is still unsatisfying. Recently, glucose oxidase (GOx) was reported to be co-delivered with Fenton agent for synergistic starvation therapy (ST) and CDT. However, the overexpressed glutathione (GSH) and hypoxia in tumor microenvironment (TME) restrict the therapeutic efficacy of ST/CDT.Methods and Results: In this work, a novel nanoplatform composed of GOx plus Fenton agent (Cu2+) encapsulated core and metformin (MET)-loaded manganese dioxide nanosheets (MNSs) shell was prepared and further functionalized by arginine-glycine-aspartate (RGD). With the RGD-mediated affinity with cancer cells, the nanocomposite (GOx-CuCaP@MNSs-MET@PEG-RGD, GCMMR) could accomplish targeting delivery and TME-activated release of cargos. The intracellular GSH was depleted by MnO2/Cu2+ and abundant H2O2 was generated along with the GOx-induced glucose deprivation, which process was further enhanced by MET-mediated hypoxia relief via inhibiting mitochondria-associated respiration. Subsequently generated •OH from Cu+-mediated Fenton-like reaction exerts severe intracellular oxidative stress and cause apoptosis. Moreover, significant inhibition of tumor growth was detected in a subcutaneous xenograft model of osteosarcoma (OS) after GCMMR treatment.Conclusion: The excellent therapeutic efficacy and biosafety of the nanoplatform were confirmed both in vitro and in vivo. Collectively, this study provides an appealing strategy with catalytic cascade enhancement on targeted ST/CDT for cancer treatment, especially for hypoxic solid tumors.Graphical Abstract: Keywords: chemodynamic therapy, starvation therapy, glucose oxidase, Fenton reaction, biomineralization, metformin

Keywords

• chemodynamic therapy
• starvation therapy
• glucose oxidase
• fenton reaction
• biomineralization
• metformin