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.

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

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

The high glutathione (GSH) content in tumor cells strongly affects the efficiency of chemodynamic therapy (CDT). Despite devoted efforts, it still remains a formidable challenge for manufacturing a tumor-specific CDT with rapid and thorough depletion of GSH. Herein, a multistage GSH-consuming and tumor-specific CDT is presented. By consuming the reserved GSH and inhibiting both the raw materials and energy supply of GSH synthesis in cancer cells, it achieves highly potent GSH exhaustion. Our used glycolysis inhibitor cuts off the specific glycolysis of tumor cells to increase the sensitivity to CDT. Furthermore, the starvation effect of glycolysis inhibitor can stimulate the protective mode of normal cells. Since the glycolysis inhibitor and nanocarrier are responsive to tumor microenvironment, this makes CDT more selective to tumor cells. Our work not only fabricates nanomedicine with GSH exhausted function for highly potent CDT but also uses metabolic differences to achieve tumor-specific therapy.

A Metabolic Multistage Glutathione Depletion Used for Tumor-Specific Chemodynamic Therapy.

Combination therapy based on different mechanisms of cell death has shown promise in tumor therapy. However, when different modalities are integrated, the maximum synergy of the therapeutic effects is often lacking in the design. Herein, we report a cancer theranostic nanomedicine formula developed by considering the mechanisms of action of ferroptosis and the photothermal effect in combination therapy. The croconaine molecule was encapsulated as both a photothermal converter and an iron-chelating agent with BSA, thus leading to biocompatible and stable Cro-Fe@BSA nanoparticles (NPs). The Cro-Fe@BSA NPs in the tumor milieu showed an activated photothermal effect leading to enhanced radical formation owing to the temperature-dependent Fenton reaction kinetics, while radical formation during ferroptosis in turn prevented the heat-induced formation of heat shock proteins and thus the self-protection mechanism of cancer cells in response to heat. The activatable photoacoustic and magnetic resonance imaging performance of the Cro-Fe@BSA NPs also enabled safe and reliable cancer theranostics. 

Coordinating the Mechanisms of Action of Ferroptosis and the Photothermal Effect for Cancer Theranostics

Chemodrug resistance is a major reason accounting for tumor recurrence. Given the mechanistic complexity of chemodrug resistance, molecular inhibitors and targeting drugs often fail to eliminate drug-resistant cancer cells, and sometimes even promote chemoresistance by activating alternative pathways. Here, by exploiting biochemical fragility of high-level but dynamically balanced cellular redox homeostasis in drug-resistant cancer cells, we design a nanosized copper/catechol-based metal-organic framework (CuHPT) that effectively disturbs this homeostasis tilting the balance toward oxidative stress. Within drug-resistant cells, CuHPT starts disassembly that is triggered by persistent consumption of cellular glutathione (GSH). CuHPT disassembly simultaneously releases two structural elements: catechol ligands and reductive copper ions (Cu+). Both of them cooperatively function to amplify the production of intracellular radical oxidative species (ROS) via auto-oxidation and Fenton-like reactions through exhausting GSH. By drastically heightening cellular oxidative stress, CuHPT exhibits selective and potent cytotoxicity to multiple drug-resistant cancer cells. Importantly, CuHPT effectively inhibits in vivo drug-resistant tumor growth and doubles the survival time of tumor-bearing mice. Thus, along with CuHPT's good biocompatibility, our biochemical, cell biological, preclinical animal model data provide compelling evidence supporting the notion that this copper-based MOF is a predesigned smart therapeutic against drug-resistant cancers through precisely deconstructing their redox homeostasis.

Copper-Based Metal-Organic Framework Overcomes Cancer Chemoresistance through Systemically Disrupting Dynamically Balanced Cellular Redox Homeostasis.

Cancer cells frequently exhibit resistance to various molecular and nanoscale drugs, which inevitably affects the drugs' therapeutic outcomes. Overexpression of glutathione (GSH) has been observed in many cancer cells, and solid evidence has corroborated the resulting tumor resistance to a variety of anticancer therapies, suggesting that this biochemical characteristic of cancer cells can be developed as a potential target for cancer treatments. The single treatment of GSH-depleting agents can potentiate the responses of the cancer cells to different cell death stimuli; therefore, as an adjunctive strategy, GSH depletion is usually combined with mainstream cancer therapies for enhancing the therapeutic outcomes. Propelled by the rapid development of nanotechnology, GSH-depleting agents can be readily constructed into anticancer nanomedicines, which have shown a steep rise over the past decade. Here, we review the common GSH-depleting nanomedicines which have been widely applied in synergistic cancer treatments in recent years. Some current challenges and future perspectives for GSH depletion-based cancer therapies are also presented. With the understanding of the structure-property relationship and action mechanisms of these biomaterials, we hope that the GSH-depleting nanotechnology will be further developed to realize more effective disease treatments and even achieve successful clinical translations.

Hai-Dong Xu

Papers

Glutathione-Depleting Nanomedicines for Synergistic Cancer Therapy.