Pd@Pt-GOx/HA as a Novel Enzymatic Cascade Nanoreactor for High-Efficiency Starving-Enhanced Chemodynamic Cancer Therapy

• Published in: ACS applied materials & interfaces Vol. 12; no. 46; pp. 51249 - 51262
• Main Authors: Ming, Jiang, Zhu, Tianbao, Yang, Wangheng, Shi, Yiran, Huang, Doudou, Li, Jingchao, Xiang, Sijin, Wang, Jingjuan, Chen, Xiaolan, Zheng, Nanfeng
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 18-11-2020
• Subjects: Animals; Apoptosis - drug effects; Biocatalysis; Biocompatible Materials - chemistry; Biocompatible Materials - pharmacokinetics; Biocompatible Materials - pharmacology; Biocompatible Materials - therapeutic use; Biological and Medical Applications of Materials and Interfaces; Cell Line, Tumor; Glucose - chemistry; Glucose - metabolism; Glucose Oxidase - chemistry; Glucose Oxidase - metabolism; Hyaluronic Acid - chemistry; Hydrogen Peroxide - chemistry; Hydrogen Peroxide - metabolism; Hydrogen-Ion Concentration; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Mice; Nanostructures - chemistry; Nanostructures - therapeutic use; Nanostructures - toxicity; Neoplasms - drug therapy; Neoplasms - pathology; Oxygen - chemistry; Palladium - chemistry; Platinum - chemistry; Reactive Oxygen Species - metabolism; Tissue Distribution; Transplantation, Homologous; enzymatic cascade reaction; tumor targeting; Pd@Pt-GOx/HA nanoreactors; starvation therapy; chemodynamic therapy
• ISSN: 1944-8244; 1944-8252
• DOI: 10.1021/acsami.0c15211

Glucose oxidase (GOx)-mediated starvation therapy has demonstrated good application prospect in cancer treatment. However, the glucose- and oxygen-depletion starvation therapy still suffers from some limitations like low therapeutic efficiency and potential side effects to normal tissues. To overcome these disadvantages, herein a novel enzymatic cascade nanoreactor (Pd@Pt-GOx/hyaluronic acid (HA)) with controllable enzymatic activities was developed for high-efficiency starving-enhanced chemodynamic cancer therapy. The Pd@Pt-GOx/HA was fabricated by covalent conjugation of GOx onto Pd@Pt nanosheets (NSs), followed by linkage with hyaluronic acid (HA). The modification of HA on Pd@Pt-GOx could block the GOx activity, catalase (CAT)-like and peroxidase (POD)-like activities of Pd@Pt, reduce the cytotoxicity to normal cells and organs, and effectively target CD44-overexpressed tumors by active targeting and passive enhanced permeability and retention (EPR) effect. After endocytosis by tumor cells, the intracellular hyaluronidase (Hyase) could decompose the outer HA and expose Pd@Pt-GOx for the enzymatic cascade reaction. The GOx on the Pd@Pt-GOx could catalyze the oxidation of intratumoral glucose by O2 for cancer starvation therapy, while the O2 produced from the decomposition of endogenous H2O2 by the Pd@Pt with the CAT-like activity could accelerate the O2-dependent depletion of glucose by GOx. Meanwhile, the upregulated acidity and H2O2 content in the tumor region generated by GOx catalytic oxidation of glucose dramatically facilitated the pH-responsive POD-like activity of the Pd@Pt nanozyme, which then catalyzed degradation of the H2O2 to generate abundant highly toxic •OH, thereby realizing nanozyme-mediated starving-enhanced chemodynamic cancer therapy. In vitro and in vivo results indicated that the controllable, self-activated enzymatic cascade nanoreactors exerted highly efficient anticancer effects with negligible biotoxicity.