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.

Traditional tumor treatments, including chemotherapy, radiotherapy, photodynamic therapy, and photothermal therapy, have been developed and used to treat different types of cancer. Recently, chemodynamic therapy (CDT) has been emerged as a novel cancer therapeutic strategy. CDT utilizes Fenton or Fenton-like reaction to generate highly cytotoxic hydroxyl radicals (·OH) from endogenous hydrogen peroxide (H2 O2 ) to kill cancer cells, which displays promising therapeutic potentials for tumor treatment. However, the low catalytic efficiency and off-target side effects of Fenton reaction limit the biomedical application of CDT. In this regard, various strategies have been implemented to potentiate CDT against tumor, including retrofitting the tumor microenvironment (e.g., increasing H2 O2 level, decreasing reductive substances, and reducing pH), enhancing the catalytic efficiency of nanocatalysts, and other strategies. This review aims to summarize the development of CDT and summarize these recent progresses of nanocatalyst-mediated CDT for antitumor application. The future development trend and challenges of CDT are also discussed. This article is protected by copyright. All rights reserved.

Nanocatalyst-Mediated Chemodynamic Tumor Therapy.

Poor targeting of therapeutics leading to severe adverse effects on normal tissues is considered one of the obstacles in cancer therapy. To help overcome this, nanoscale drug delivery systems have provided an alternative avenue for improving the therapeutic potential of various agents and bioactive molecules through the enhanced permeability and retention (EPR) effect. Nanosystems with cancer-targeted ligands can achieve effective delivery to the tumor cells utilizing cell surface-specific receptors, the tumor vasculature and antigens with high accuracy and affinity. Additionally, stimuli-responsive nanoplatforms have also been considered as a promising and effective targeting strategy against tumors, as these nanoplatforms maintain their stealth feature under normal conditions, but upon homing in on cancerous lesions or their microenvironment, are responsive and release their cargoes. In this review, we comprehensively summarize the field of active targeting drug delivery systems and a number of stimuli-responsive release studies in the context of emerging nanoplatform development, and also discuss how this knowledge can contribute to further improvements in clinical practice. 

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Enhancing the therapeutic efficacy of nanoparticles for cancer treatment using versatile targeted strategies

The increasing cancer morbidity and mortality requires the development of high-efficiency and low-toxicity anticancer approaches. In recent years, photodynamic therapy (PDT) has attracted much attention in cancer therapy due to its non-invasive features and low side effects. Photosensitizer (PS) is one of the key factors of PDT, and its successful delivery largely determines the outcome of PDT. Although a few PS molecules have been approved for clinical use, PDT is still limited by the low stability and poor tumor targeting capacity of PSs. Various nanomaterial systems have shown great potentials in improving PDT, such as metal nanoparticles, graphene-based nanomaterials, liposomes, ROS-sensitive nanocarriers and supramolecular nanomaterials. The small molecular PSs can be loaded in functional nanomaterials to enhance the PS stability and tumor targeted delivery, and some functionalized nanomaterials themselves can be directly used as PSs. Herein, we aim to provide a comprehensive understanding of PDT, and summarize the recent progress of nanomaterials-based PSs and delivery systems in anticancer PDT. In addition, the concerns of nanomaterials-based PDT including low tumor targeting capacity, limited light penetration, hypoxia and nonspecific protein corona formation are discussed. The possible solutions to these concerns are also discussed. 

Nanomaterials-based photosensitizers and delivery systems for photodynamic cancer therapy.

Chemodynamic therapy is a promising cancer treatment with specific therapeutic effect at tumor sites, as toxic hydroxyl radical (·OH) could only be generated by Fenton or Fenton-like reaction in the tumor microenvironment (TME) with low pH and high level of endogenous hydrogen peroxide. However, the low concentration of catalytic metal ions, excessive glutathione (GSH) and aggressive hypoxia at tumor site seriously restrict the curative outcomes of conventional chemodynamic therapy.In this study, polyethylene glycol-phenylboronic acid (PEG-PBA)-modified generation 5 (G5) poly(amidoamine) (PAMAM) dendrimers were synthesized as a targeted nanocarrier to chelate Cu(II) and then encapsulate hypoxia-sensitive drug tirapazamine (TPZ) by the formation of hydrophobic Cu(II)/TPZ complex for hypoxia-enhanced chemo/chemodynamic therapy. The formed G5.NHAc-PEG-PBA@Cu(II)/TPZ (GPPCT) nanoplatform has good stability and hemocompatibility, and could release Cu(II) ions and TPZ quickly in weakly acidic tumor sites via pH-sensitive dissociation of Cu(II)/TPZ. In vitro experiments showed that the GPPCT nanoplatforms can efficiently target murine breast cancer cells (4T1) cells overexpressing sialic acid residues, and show a significantly enhanced inhibitory effect on hypoxic cells by the activation of TPZ. The excessive GSH in tumors could be depleted by the reduction of Cu(II) to Cu(I), and abundant of toxic ·OH would be generated in tumor cells by Fenton reaction for chemodynamic therapy. In vivo experiments demonstrated that the GPPCT nanoplatform could specifically accumulate at tumors, effectively inhibit the growth and metastasis of tumors by the combination of CDT and chemotherapy, and be metabolized with no systemic toxicity.The targeted GPPCT nanoplatform may represent an effective model for the synergistic inhibition of different tumor types by hypoxia-enhanced chemo/chemodynamic therapy. 

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A tumor microenvironment-responsive poly(amidoamine) dendrimer nanoplatform for hypoxia-responsive chemo/chemodynamic therapy

Ferrocene-containing polymersome nanoreactors for synergistically amplified tumor-specific chemodynamic therapy.

Hypoxia-responsive block copolymer polyprodrugs for complementary photodynamic-chemotherapy

Targeting delivery of anticancer drugs that can interact with DNA into mitochondria of cancer cells has been demonstrated to be an effective method to combat drug resistance. In this report, a cancer cell and mitochondria dual-targeting drug delivery system (DT-NP) is presented based on nanoparticles self-assembled from amphiphilic block copolymers with pH-responsive release of cinnamaldehyde (CA), which is used to encapsulate reactive oxygen species (ROS)-activable prodrug, phenylboronic pinacol ester-caged doxorubicin (BDOX). The surfaces of nanoparticles are conjugated by cancer cell-targeting folic acid (FA) and mitochondria-targeting triphenyl phosphonium (TPP) for dual targeting delivery. After incubation of DT-NP with multidrug-resistant breast cancer cells MCF-7/ADR, CA release under acidic conditions in endosomes from DT-NP can effectively induce intracellular oxidative stress improvement, especially in mitochondria. After targeting drug delivery into mitochondria, high level of ROS in mitochondria can in situ activate BDOX to interact with mitochondrial DNA and induce cell apoptosis. DT-NP displays a remarkably higher cancer cell killing effect on MCF-7/ADR as compared with DOX. Accordingly, DT-NP shows great potentials toward multidrug-resistant cancers as dual-targeting drug delivery systems with intracellular oxidative stress improvement and ROS-responsive prodrug activation in mitochondria.

Dual-Targeting Polymeric Nanocarriers to Deliver ROS-Responsive Prodrugs and Combat Multidrug Resistance of Cancer Cells.

Photodynamic therapy (PDT) of cancers is seriously restricted by tumor hypoxia. In addition to the intrinsic hypoxic microenvironment, continuous photoirradiation further aggravates intratumoral hypoxia, thereby reducing the PDT effect significantly. Oxygen-independent PDT is recognized as an efficient approach to overcome this issue. Herein, singlet oxygen (1 O2 )-stored covalent organic framework (COF) nanoparticles loading the near-infrared (NIR) dye cypate, which realize oxygen-independent 1 O2 production for concurrent photothermal therapy (PTT) and PDT under NIR irradiation, are presented. The cypate-loading COF nanoparticles are prepared by using the photosensitizers and 1 O2 -stored molecules via formation of Schiff base bonds, followed by coverage of poly(vinyl pyrrolidone). The COF nanoparticles significantly improve the photostability and photothermal conversion efficiency of cypate by protecting them from photodegradation under NIR irradiation. Upon 660 nm laser irradiation, 1 O2 is produced by the photosensitizer motifs and is successfully stored by the 1 O2 -stored moieties. After intravenous injection and tumor accumulation, the COF nanoparticles can generate heat quickly upon 808 nm irradiation which induces the efficient release of the stored 1 O2 to ablate tumors via O2 -independent concurrent PTT/PDT. Accordingly, the COF nanocarriers of 1 O2 provide a paradigm to develop O2 -independent concurrent PTT/PDT for precise cancer treatment upon NIR irradiation.

Covalent Organic Framework Nanocarriers of Singlet Oxygen for Oxygen-Independent Concurrent Photothermal/Photodynamic Therapy to Ablate Hypoxic Tumors.

Nanofibers self-assembled from peptides have attracted much attention to inhibit cancer cells. However, there are still some disadvantages, including high concentration for self-assembly and incapability to load drugs, which limit their applications. In this report, we rationally integrate self-assembled peptides, glutathione-sensitive disulfide bonds, and mitochondrial targeting moieties into the amphiphilic block copolymer to construct the nanocarriers, which can be used to load anticancer drug doxorubicin (DOX). After cellular internalization, the nanocarriers can reassemble from micelles to nanofibers under the trigger by glutathione and locate in mitochondria. The released DOX and nanofibers induce mitochondrial dysfunction and activate the apoptosis pathway to synergistically inhibit tumor cells. This organelle-specific drug delivery system with reassembly capability from micelles to nanofibers shows great potential for effectively killing cancer cells.

Jingbo Wang

Papers

Ferrocene-containing polymersome nanoreactors for synergistically amplified tumor-specific chemodynamic therapy.

Hypoxia-responsive block copolymer polyprodrugs for complementary photodynamic-chemotherapy

Dual-Targeting Polymeric Nanocarriers to Deliver ROS-Responsive Prodrugs and Combat Multidrug Resistance of Cancer Cells.

Covalent Organic Framework Nanocarriers of Singlet Oxygen for Oxygen-Independent Concurrent Photothermal/Photodynamic Therapy to Ablate Hypoxic Tumors.

Glutathione-Triggered Mitochondria-Targeting Reassembly from Polymeric Micelles to Nanofibers for a Synergistic Anticancer Effect.