Chemodynamic therapy (CDT) has emerged to be a frontrunner amongst reactive oxygen species-based cancer treatment modalities. CDT utilizes endogenous H2O2 in tumor microenvironment (TME) to produce cytotoxic hydroxyl radicals (•OH) via Fenton or Fenton-like reactions. While possessing advantages such as tumor specificity, no need of external stimuli, and low side effects, practical applications of CDT are still impeded owing to the heterogeneity, complexity, and reductive environment of TME. Over the past couple of years, strategies to enhance CDT for efficient tumor regression are in rapid development in synergy with the growth of nanomedicine. In this review, we initially outline the fundamental understanding of Fenton and Fenton-like reactions and their relationship with CDT. Subsequently, the development in the design of nanosystems for CDT is highlighted in a general manner. Furthermore, recent advancement of the strategies to augment Fenton reactions in TME for enhanced CDT is discussed in detail. Finally, perspectives toward the future development of CDT for better therapeutic outcome are presented. This review is expected to draw attention for collaborative research on CDT in the best interest of its future clinical applications. 

Strategies for enhancing cancer chemodynamic therapy performance

Two-dimensional (2D) metal-organic framework (MOF) nanosheets have been demonstrated to be promising templates for the growth of various kinds of nanomaterials on their surfaces to construct novel 2D composites, thus realizing enhanced performance in various applications. Herein, we report the growth of Cu2O nanoparticles on 2D Zr-ferrocene (Zr-Fc)-MOF (Zr-Fc-MOF) nanosheets to prepare 2D composites for near-infrared (NIR) photothermally enhanced chemodynamic antibacterial therapy. The uniform Zr-Fc-MOF nanosheets are synthesized using the solvothermal method, followed by ultrasound sonication, and Cu2O nanoparticles are then deposited on its surface to obtain the Cu2O-decorated Zr-Fc-MOF (denoted as Cu2O/Zr-Fc-MOF) 2D composite. Promisingly, the Cu2O/Zr-Fc-MOF composite shows higher chemodynamic activity for producing ·OH via Fenton-like reaction than that of the pristine Zr-Fc-MOF nanosheets. More importantly, the chemodynamic activity of the Cu2O/Zr-Fc-MOF composite can be further enhanced by the photothermal effect though NIR laser (808 nm) irradiation. Thus, the Cu2O/Zr-Fc-MOF composite can be used as an efficient nanoagent for photothermally enhanced chemodynamic antibacterial therapy.

Growth of Cu2O Nanoparticles on Two-Dimensional Zr-Ferrocene-Metal-Organic Framework Nanosheets for Photothermally Enhanced Chemodynamic Antibacterial Therapy.

Recent advances in nano-architectonics of metal-organic frameworks for chemodynamic therapy

Artificial photocatalysis offers a clean approach for producing H2O2. However, the poor selectivity and activity of H2O2 production hamper traditional industrial applications and emerging photodynamic therapy (PDT)/chemodynamic therapy (CDT). Here, we report a C5N2 photocatalyst with a conjugated C=N linkage for selective and efficient non-sacrificial H2O2 production both in normoxic and hypoxic systems. The strengthened delocalization of π-electrons by linkers in C5N2 downshifted the band position, thermodynamically eliminating the side H2 evolution and kinetically promoting the water oxidation. As a result, C5N2 had a competitive solar-to-chemical conversion efficiency of 0.55% in overall H2O2 production and exhibited by far the highest activity in hypoxic conditions (698 μM/h). C5N2 was further applied to hypoxic PDT/CDT with outstanding performance in apparent cancer cell death and synchronous bioimaging. It sheds light on carbon nitrides in photosynthesizing H2O2 for health.

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Extended Conjugation Refining Carbon Nitride for Non-sacrificial H2O2 Photosynthesis and Hypoxic Tumor Therapy.

Tumor microenvironment (TME)‐activated cancer imaging and therapy is a key to achieving accurate diagnosis and treatment of cancer and reducing the side effects. Herein, smart near‐infrared carbon dot‐metal organic framework MIL‐100 (Fe) assemblies are constructed to achieve TME‐activated cancer imaging and chemodynamic‐photothermal combined therapy. First, a near‐infrared emission carbon dot (RCDs) is developed using glutathione (GSH) as the precursor. Then, the RCDs@MIL‐100 self‐assemblies are obtained using RCDs, FeCl3, and trimesic acid solutions as raw materials. After the RCDs@MIL‐100 enters the TME, a high concentration of GSH reduces Fe3+ to Fe2+ and drains the GSH, triggering the collapse of RCDs@MIL‐100 skeleton and the release of RCDs and Fe2+, at which time the RCDs fluorescence is restored and in an “on” state to illuminate the tumor cells, which achieved cancer imaging. The released Fe2+ reacts with H2O2 in the TME to form highly reactive hydroxyl radicals (•OH) by Fenton reaction, which achieves the chemodynamic therapy of tumors. Thus, efficient synergistic chemodynamic‐photothermal dual mode therapy is achieved under fluorescence imaging guidance with TME response.

A Smart Near‐Infrared Carbon Dot‐Metal Organic Framework Assemblies for Tumor Microenvironment‐Activated Cancer Imaging and Chemodynamic‐Photothermal Combined Therapy

Chemodynamic therapy (CDT), a novel cancer therapeutic strategy defined as the treatment using Fenton or Fenton-like reaction to produce •OH in the tumor region, was first proposed by Bu, Shi, and co-workers in 2016. Recently, with the rapid development of Fenton and Fenton-like nanomaterials, CDT has attracted tremendous attention because of its unique advantages: 1) It is tumor-selective with low side effects; 2) the CDT process does not depend on external field stimulation; 3) it can modulate the hypoxic and immunosuppressive tumor microenvironment; 4) the treatment cost of CDT is low. In addition to the Fe-involved CDT strategies, the Fenton-like reaction-mediated CDT strategies have also been proposed, which are based on many other metal elements including copper, manganese, cobalt, titanium, vanadium, palladium, silver, molybdenum, ruthenium, tungsten, cerium, and zinc. Moreover, CDT has been combined with other therapies like chemotherapy, radiotherapy, phototherapy, sonodynamic therapy, and immunotherapy for achieving enhanced anticancer effects. Besides, there have also been studies that extend the application of CDT to the antibacterial field. This review introduces the latest advancements in the nanomaterials-involved CDT from 2018 to the present and proposes the current limitations as well as future research directions in the related field.

Chenyang Jia

Papers

Chemodynamic Therapy via Fenton and Fenton-Like Nanomaterials: Strategies and Recent Advances.