Glutathione Depletion-Induced ROS/NO Generation for Cascade Breast Cancer Therapy and Enhanced Anti-Tumor Immune Response

Abstract

Jing Wang,1,* Yanxiang Sang,2,* Weijian Chen,3 Liang Cheng,2 Wenxiang Du,2 Hongjie Zhang,2 Benyan Zheng,2 Lei Song,2 Yuan Hu,2 Xiaopeng Ma1 1Department of General Surgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, People’s Republic of China; 2State Key Laboratory of Fire Science, University of Science and Technology of China, Hefei, Anhui, 230006, People’s Republic of China; 3Technology Center, China Tobacco Anhui Industrial Co, Ltd, Hefei, Anhui, 230088, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yuan Hu; Xiaopeng Ma, Email [email protected]; [email protected]: As an effective alternative choice to traditional mono-therapy, multifunctional nanoplatforms hold great promise for cancer therapy. Based on the strategies of Fenton-like reactions and reactive oxygen species (ROS)-mediated therapy, black phosphorus (BP) nanoplatform BP@Cu2O@L-Arg (BCL) co-assembly of cuprous oxide (Cu2O) and L-Arginine (L-Arg) nanoparticles was developed and evaluated for synergistic cascade breast cancer therapy.Methods: Cu2O particles were generated in situ on the surface of the BP nanosheets, followed by L-Arg incorporation through electrostatic interactions. In vitro ROS/nitric oxide (NO) generation and glutathione (GSH) depletion were evaluated. In vitro and in vivo anti-cancer activity were also assessed. Finally, immune response of BCL under ultrasound was investigated.Results: Cu2O was incorporated into BP to exhaust the overexpressed intracellular GSH in cancer cells via the Fenton reaction, thereby decreasing ROS consumption. Apart from being used as biocompatible carriers, BP nanoparticles served as sonosensitizers to produce excessive ROS under ultrasound irradiation. The enhanced ROS accumulation accelerated the oxidation of L-Arg, which further promoted NO generation for gas therapy. In vitro experiments revealed the outstanding therapeutic killing effects of BCL under ultrasound via mechanisms involving GSH deletion and excessive ROS and NO generation. In vivo studies have illustrated that the nanocomplex modified the immune response by promoting macrophage and CD8+ cell infiltration and inhibiting MDSC infiltration.Discussion: BCL nanoparticles exhibited multifunctional characteristics for GSH depletion-induced ROS/NO generation, making a new multitherapy strategy for cascade breast cancer therapy.Keywords: black phosphorus, combination cancer therapy, sonodynamic therapy, chemodynamic therapy, nitric oxide gas therapy

Keywords

• black phosphorus
• combination cancer therapy
• sonodynamic therapy
• chemodynamic therapy
• nitric oxide gas therapy