Chemodynamic therapy (CDT) uses the tumor microenvironment-assisted intratumoral Fenton reaction for generating highly toxic hydroxyl free radicals (•OH) to achieve selective tumor treatment. However, the limited intratumoral Fenton reaction efficiency restricts the therapeutic efficacy of CDT. Recent years have witnessed the impressive development of various strategies to increase the efficiency of intratumoral Fenton reaction. The introduction of these reinforcement strategies can dramatically improve the treatment efficiency of CDT and further promote the development of enhanced CDT (ECDT)-based multimodal anticancer treatments. In this review, the authors systematically introduce these reinforcement strategies, from their basic working principles, reinforcement mechanisms to their representative clinical applications. Then, ECDT-based multimodal anticancer therapy is discussed, including how to integrate these emerging Fenton reinforcement strategies for accelerating the development of multimodal anticancer therapy, as well as the synergistic mechanisms of ECDT and other treatment methods. Eventually, future direction and challenges of ECDT and ECDT-based multimodal synergistic therapies are elaborated, highlighting the key scientific problems and unsolved technical bottlenecks to facilitate clinical translation.

Manipulating Intratumoral Fenton Chemistry for Enhanced Chemodynamic and Chemodynamic-Synergized Multimodal Therapy.

Applying Fenton chemistry in the tumor microenvironment (TME) for cancer therapy is the most significant feature of chemodynamic therapy (CDT). Owing to the mild acid and overexpressed H2O2 in TME, more cytotoxic hydroxyl radicals (·OH) are generated in tumor cells via Fenton and Fenton-like reactions. Without external stimulus and drug resistance generation, reactive oxygen species (ROS)-mediated CDT exhibits a specific and desirable anticancer effect and has been seen as a promising strategy for cancer therapy. However, optimizing the treatment efficiency of CDT in TME is still challenging because of the limited catalytic efficiency of CDT agents and the strong cancer antioxidant capacity in TME. Hence, scientists are trying their best to design and fabricate many more CDT agents with excellent catalytic activity and remodeling TME for optimal CDT. In this perspective, the latest progress of CDT is discussed, with some representative examples presented. Consequently, promising strategies for further optimizing the efficiency of CDT guided by Fenton chemistry are provided. Most importantly, several feasible ways of developing CDT in the future are offered for reference.

Recent Advances of Cancer Chemodynamic Therapy Based on Fenton/Fenton-like Chemistry

Applying Fenton chemistry in the tumor microenvironment (TME) for cancer therapy is the most significant feature of chemodynamic therapy (CDT). Owing to the mild acid and overexpressed H2O2 in TME, more cytotoxic hydroxyl radicals (˙OH) are generated in tumor cells via Fenton and Fenton-like reactions. Without external stimulus and drug resistance generation, reactive oxygen species (ROS)-mediated CDT exhibits a specific and desirable anticancer effect and has been seen as a promising strategy for cancer therapy. However, optimizing the treatment efficiency of CDT in TME is still challenging because of the limited catalytic efficiency of CDT agents and the strong cancer antioxidant capacity in TME. Hence, scientists are trying their best to design and fabricate many more CDT agents with excellent catalytic activity and remodeling TME for optimal CDT. In this perspective, the latest progress of CDT is discussed, with some representative examples presented. Consequently, promising strategies for further optimizing the efficiency of CDT guided by Fenton chemistry are provided. Most importantly, several feasible ways of developing CDT in the future are offered for reference. 

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Recent advances of cancer chemodynamic therapy based on Fenton/Fenton-like chemistry

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

Against the backdrop of increased public health awareness, inorganic nanomaterials have been widely explored as promising nanoagents for various kinds of biomedical applications. Layered double hydroxides (LDHs), with versatile physicochemical advantages including excellent biocompatibility, pH-sensitive biodegradability, highly tunable chemical composition and structure, and ease of composite formation with other materials, have shown great promise in biomedical applications. In this review, we comprehensively summarize the recent advances in LDH-based nanomaterials for biomedical applications. Firstly, the material categories and advantages of LDH-based nanomaterials are discussed. The preparation and surface modification of LDH-based nanomaterials, including pristine LDHs, LDH-based nanocomposites and LDH-derived nanomaterials, are then described. Thereafter, we systematically describe the great potential of LDHs in biomedical applications including drug/gene delivery, bioimaging diagnosis, cancer therapy, biosensing, tissue engineering, and anti-bacteria. Finally, on the basis of the current state of the art, we conclude with insights on the remaining challenges and future prospects in this rapidly emerging field.

Yurui Wang

Papers

Recent advances in enhanced chemodynamic therapy strategies