REVIEW ARTICLE

Hydroxyl radical-involved cancer therapy via Fenton reactions

  • Mengying Liu 1 ,
  • Yun Xu 2 ,
  • Yanjun Zhao 1 ,
  • Zheng Wang , 1 ,
  • Dunyun Shi , 3
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  • 1. School of Pharmaceutical Science & Technology, Tianjin University, Tianjin 300072, China
  • 2. Central Lab, Shenzhen Second People’s Hospital/the First Affiliated Hospital of Shenzhen University, Shenzhen 518035, China
  • 3. Institute of Hematology, Shenzhen Second People’s Hospital/the First Affiliated Hospital of Shenzhen University, Shenzhen 518035, China

Received date: 03 Feb 2021

Accepted date: 01 Jun 2021

Published date: 15 Mar 2022

Copyright

2021 Higher Education Press

Abstract

The tumor microenvironment features over-expressed hydrogen peroxide (H2O2). Thus, versatile therapeutic strategies based on H2O2 as a reaction substrate to generate hydroxyl radical (•OH) have been used as a prospective therapeutic method to boost anticancer efficiency. However, the limited Fenton catalysts and insufficient endogenous H2O2 content in tumor sites greatly hinder •OH production, failing to achieve the desired therapeutic effect. Therefore, supplying Fenton catalysts and elevating H2O2 levels into cancer cells are effective strategies to improve •OH generation. These therapeutic strategies are systematically discussed in this review. Furthermore, the challenges and future developments of hydroxyl radical-involved cancer therapy are discussed to improve therapeutic efficacy.

Cite this article

Mengying Liu , Yun Xu , Yanjun Zhao , Zheng Wang , Dunyun Shi . Hydroxyl radical-involved cancer therapy via Fenton reactions[J]. Frontiers of Chemical Science and Engineering, 2022 , 16(3) : 345 -363 . DOI: 10.1007/s11705-021-2077-3

1 Introduction

Currently, the high mortality rate of cancer is a big threat to human health because of its complexity and versatility [1]. In this regard, scientific research on efficient cancer therapy is necessary. Therefore, the development of various effective anticancer agents has become a top priority. In recent years, reactive oxygen species (ROS) [2], including superoxide anion (O2•−) [3], hydrogen peroxide (H2O2) [4], hydroxyl radical (•OH) [5], and singlet oxygen (1O2) [6], have been considered as important therapeutic agents for cancer therapy because of their ability to induce cancer apoptosis. The traditional ROS-based therapies, such as photodynamic therapy [7], radiotherapy [8], and sonodynamic therapy [9], require exogenous energy input to induce cancer cell death, resulting in serious damage to surrounding normal tissues or cells. However, chemodynamic therapy utilizes endogenous chemical reactions between Fenton catalysts and H2O2 to produce •OH without external energy input [10]. Therefore, damage on normal cells or tissues can be avoided. The content of H2O2 in cancer cells is higher than that in normal cells. The H2O2 content in tumor cells is approximately 0.1–1 mmol·L−1 [11], whereas that in normal cells is nearly 1–8 μmol·L−1 in a dynamic balance [12,13]. Nevertheless, the •OH generation depends not only on intracellular H2O2 content but also on the Fenton catalysts. As a classical Fenton catalyst, iron ions can trigger •OH generation by reacting with over-produced H2O2 in tumor cells [1416]. Free iron ions in cells are low and primarily found in ferritin and hemosiderin proteins [17,18]. Thus, iron-based nanocarriers have been extensively fabricated to transport iron ions into cells, thereby increasing •OH generation [1922].
Apart from iron-based Fenton catalysts, other metal-based catalysts can be used to generate •OH through Fenton-like reactions, such as Mn-based Fenton catalysts and Cu-based Fenton catalysts. Once internalized by cancer cells, the Fenton catalyst-based nanocarriers could be degraded and release Fenton catalysts in the acidic tumor microenvironment, thereby catalyzing intracellular H2O2 decomposition and generating abundant toxic •OH (Fig. 1). These typical metal catalysts have been widely studied, and they have shown excellent •OH generation for inducing cancer oxidative stress and apoptosis [2326]. Although tumor cells are characterized by the overexpression of H2O2, the amount of •OH needed to achieve the desired therapeutic outcomes still cannot be produced. Therefore, elevating H2O2 levels to produce considerable •OH is a feasible approach to improve therapeutic effectiveness. Many strategies have been designed to elevate H2O2 levels in tumor sites for cancer treatment [2733].
Fig.1 Schematic illustration of •OH-mediated cancer therapy.

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This review aims to highlight different strategies for boosting •OH generation. On one hand, we focus on the supply of typical metal-based Fenton catalysts to promote •OH generation. On the other hand, we emphasize on the synergistic elevation of H2O2 level to boost •OH generation, thereby achieving satisfactory therapeutic performance. Finally, the limitations and improvement of hydroxyl radical-based cancer therapy are also discussed.

2 Introduction of Fenton catalysts

Intracellular H2O2 can be converted into •OH by introducing Fenton catalysts. Therefore, supplying Fenton catalysts to the tumor sites is an effective strategy to promote •OH generation. Many research groups have investigated the efficacy of classical metal Fenton catalyst-based nanocarriers to enable •OH generation (shown in Table 1).
Tab.1 The supply of Fenton catalysts and elevation of H2O2 level for enhanced •OH generation a)
Material Functional mechanism Cell Ref.
IONPs Fe2+-mediated •OH generation HT1080 [34]
JFSNs-GOx GOx-catalyzed H2O2 generation; Fe2+-mediated •OH generation 4T1 [35]
CPT@MOF(Fe)-GOx GOx-catalyzed H2O2 generation; Fe2+-mediated •OH generation; CPT-mediated chemotherapy HeLa [36]
rFeOx-HMSN Fe2+-mediated •OH generation 4T1 [37]
LET-6 Fe2+-mediated •OH generation;
tPy-Cy-Fe-mediated photothermal therapy
U87MG [38]
Fe5C2@Fe3O4 NPs Fe2+-mediated •OH generation 4T1 [39]
FDMSNs@GOx@HA GOx-catalyzed H2O2 generation; Fe2+-mediated •OH generation L-02; HeLa [40]
Fe-CO@Mito-PNBE CO-mediated gas therapy; Fe2+-mediated •OH generation 4T1; HeLa [41]
CuS-Fe@polymer Fe2+-mediated •OH generation; CuS-mediated photothermal therapy HeLa; NIH3T3 [42]
Co-Fc@GOx GOx-catalyzed H2O2 generation; Fe2+-mediated •OH generation HUVEC; 4T1 [43]
Zr-Fc MOF Zr-Fc MOF-mediated photothermal therapy; Fe2+-mediated •OH generation 7702; 4T1; Huh7 [44]
CFNCs Fe2+-mediated •OH generation; PTX-mediated chemotherapy HCT-15; NIH3T3 [45]
GOx&Pt@FcNV GOx-catalyzed H2O2 generation; Fe2+-mediated •OH generation; Pt-mediated chemotherapy A549; MCF7 [46]
GOx@ZIF@MPN GOx-catalyzed H2O2 generation; Fe2+-mediated •OH generation 4T1 [47]
BSO/GA-Fe(II)@liposome BSO-mediated GSH synthesis inhibition; Fe2+-mediated •OH generation 4T1 [48]
SRF@FeIIITA SRF-mediated GSH synthesis inhibition; Fe2+-mediated •OH generation 4T1; CT26; HepG2; 3T3; COS7;
NCTC 1469
[49]
Fe3+-DOX@EGCG-PEG NPs DOX-mediated chemotherapy; Fe2+-mediated •OH generation U87MG; 293T [50]
DOX/Fe3+/EGCG NPs DOX-mediated chemotherapy; Fe2+-mediated •OH generation LL2; A549 [51]
MnS@BSA H2S-mediated gas therapy; Mn2+-mediated •OH generation 4T1 [52]
GOx-MnCaP-DOX GOx-catalyzed H2O2 generation; Mn2+-mediated •OH generation; DOX-mediated chemotherapy 4T1 [53]
GNR@SiO2@MnO2 Mn2+-mediated •OH generation; GSM-mediated photothermal therapy U87MG [54]
BMC-DOX Mn2+-mediated •OH generation; DOX-mediated chemotherapy 4T1; U87MG [55]
GMCD GOx-catalyzed H2O2 generation; Mn2+-mediated •OH generation; CAT-mediated O2 generation; DVDMS-mediated 1O2 generation 4T1 [56]
MS@MnO2 NPs MnO2-mediated GSH depletion; Mn2+-mediated •OH generation U87MG [57]
PCN-224(Cu)-GOD@MnO2 MnO2-mediated O2 supply; GOD-mediated H2O2 generation; Cu+-mediated •OH generation L929; HeLa [58]
Cu2–xS-PEG NDs Cu2–xS-mediated photothermal therapy; Cu+-mediated •OH generation 4T1 [59]
PEG-Cu2Se HNCs Cu2Se-mediated photothermal therapy; Cu+-mediated •OH generation HUVECs; 4T1 [60]
PGC-DOX GOx-catalyzed H2O2 generation; Cu2+-mediated GSH depletion; Cu+-mediated •OH generation; DOX-mediated chemotherapy 4T1 [61]
SC@G NSs GOx-catalyzed H2O2 generation; Sr+/Cu+-mediated •OH generation; SC NSs-mediated photothermal therapy 4T1; 293T [62]
Cu-Cys NPs Cu2+-mediated GSH depletion; Cu+-mediated •OH generation HeLa; MCF-7; PC-3; hADSCs; hbMSCs; HK-2 [63]
GOD-Fe3O4@DMSNs GOD-catalyzed H2O2 generation; Fe2+-mediated •OH generation 4T1; U87 [64]
MNS-GOx GOx-catalyzed H2O2 generation; Mn2+-mediated •OH generation A375 [65]
Fe5C2-GOD@MnO2 MnO2-mediated O2 supply; GOD-mediated H2O2 generation; Fe2+-mediated •OH generation HeLa [66]
PEG-Au/FeMOF@CPT NPs Au-catalyzed H2O2 generation; Fe2+-mediated •OH generation; CPT-mediated chemotherapy HepG2 [67]
DMSN-Au-Fe3O4-PEG NPs Au-catalyzed H2O2 generation; Fe2+-mediated •OH generation 4T1 [68]
Fe3O4@PEI-Pt(IV)-PEG SOD-catalyzed H2O2 generation; Fe2+-mediated •OH generation; Pt-mediated chemotherapy A2780; ACP [69]
PZIF67-AT As nanozyme, ZIF-67-mediated H2O2 generation, •OH generation, and GSH depletion; 3-AT-mediated H2O2 elimination inhibition A549; HeLa; 4T1 [70]
PA/Fc-Micelles Asc-mediated H2O2 generation; Fe2+-mediated •OH generation 4T1; MCF-7 [71]
CaP-Fe/RSL3+ Asc Asc-mediated H2O2 generation; Fe2+-mediated •OH generation; RSL3-mediated GPX4 inhibition 4T1 [72]
CaO2-Fe3O4@HA NPs CaO2-mediated H2O2 generation; Fe2+-mediated •OH generation 4T1; NIH/3T3; LO2; MCF-7 [73]
Nb2C-IO-CaO2-PVP CaO2-mediated H2O2 generation; Fe2+-mediated •OH generation 4T1 [74]
CP nanodots CP nanodots
-mediated H2O2 generation and •OH generation
U87MG [75]
Fe-GA/CaO2@PCM PCMs-mediated photothermal-responsive gatekeeper; CaO2-mediated H2O2 generation; Fe2+-mediated •OH generation HeLa [76]
HA-CD/Fc-CA NPs CA-mediated H2O2 generation; Fe2+-mediated •OH generation MCF-7; 4T1; NIH/3T3 [77]
PolyCAFe CA-mediated H2O2 generation; Fe2+-mediated •OH generation SW620; DU145; HEK293; NIH3T3 [78]
LaCIONPs La-mediated H2O2 generation; Fe2+-mediated •OH generation; CPT-mediated chemotherapy A549 [79]
PtkDOX-NMs La-mediated H2O2 generation; Fe2+-mediated •OH generation; DOX-mediated chemotherapy A549 [80]
Fe3O4-HSA@Lapa La-mediated H2O2 generation; Fe2+-mediated •OH generation A549 [81]
Fe@Fe3O4@Cu2–xS@La-PEG La-mediated H2O2 generation; Fe@Fe3O4@Cu2–xS-PEG-mediated •OH generation 4T1; HUVE [82]

a) GOD or GOx: glucose oxidase; La: β-lapachone; CA: cinnamaldehyde; CAT: catalase; GPX: glutathione peroxidase; NP: nanoparticle; Fc: ferrocene; DOX: doxorubicin; GSH: glutathione; Asc: ascorbate; GA: gallic acid; PCMs: phase change materials; MOF: metal-organic framework; EGCG: epigallocatechin gallate; ZIF: zeolite imidazole framework; 3-AT: 3-amino-1,2,4-triazole.

According to the sources of Fenton catalysts, three classical metal types are mainly summarized in Fig. 2: Fe-based Fenton catalysts, Mn-based Fenton catalysts, and Cu-based Fenton catalysts. We review the Fenton catalysts based on three types in the following.
Fig.2 Three typical metal-based catalysts for the Fenton reaction.

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2.1 Fe-based Fenton catalysts

Iron ions as the classical Fenton catalyst have been extensively applied in •OH generation. With the development of nanotechnology, various nanocarriers have been developed and applied in antitumor therapy [8385]. Fe-based nanocarriers have been constructed and proven effective in generating •OH because of the presence of iron ions, including iron oxide NPs [34,35,86], iron-based metal-organic frameworks [36], and other iron-based nanocarriers [37,38]. These iron-based nanocarriers have good magnetic targeting ability, specifically targeting cancer cells. Hence, iron-based nanocarriers could accumulate at the tumor sites to target the release of iron ions, thereby promoting •OH production. Moreover, the released iron ions show the function of nuclear magnetic imaging, monitoring the therapeutic process.
As an example for iron oxide NPs, Yu et al. constructed pH-sensitive Fe5C2@Fe3O4 NPs that could be adequately decomposed, promoting the release of Fe2+ in acidic tumor conditions. As shown in Fig. 3, the constructed Fe5C2@Fe3O4 nanocarriers had high sensitivity to the acidity of tumor sites, effectively releasing Fe2+ in tumor regions. The released Fe2+ could react with overexpressed H2O2 to produce •OH, specifically killing cancer cells and showing an excellent antitumor effect. Considering that the release of iron ions from Fe5C2@Fe3O4 depended on low pH, the toxicity of Fe5C2@Fe3O4 was minimal in normal cells [39]. The designed nanocarriers provided a new strategy for efficient and specific cancer therapy based on the selective catalysis of •OH generation.
Fig.3 Schematic diagram of the therapeutic mechanism of Fe5C2@Fe3O4 NPs. Reprinted with permission from ref. [39]. Copyright 2019, American Chemical Society.

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In addition to Fe-based nanocarriers, Fc and its derivatives can generate •OH and simultaneously release Fe2+ in the presence of H2O2 and H+. Therefore, numerous nanocarriers designed on the basis of Fc and its derivatives have been applied in anticancer treatments [4045,87]. For example, Chen et al. constructed a new nanodrug (GOx&Pt@FcNV) using a Fc-containing nanovesicle. As shown in Fig. 4, the GOx&Pt@FcNV nanodrug could deliver GOx, Fc and cisplatin (Pt) into the tumor sites. The GOx-mediated starvation therapy could consume intracellular glucose to concurrently generate H2O2 and H+, accelerating the release of Fe2+ from Fc. The released Fe2+ could catalyze H2O2 decomposition into •OH, resulting in the apoptosis of cancer cells. Moreover, the Pt-mediated chemotherapy would enhance the therapeutic effect [46]. This designed therapeutic strategy offered a new angle for the endogenous stimuli-activated nanocarriers to combat multidrug-resistant tumors.
Fig.4 Schematic illustration of the mechanisms of GOx&Pt@FcNV against tumors. Reprinted with permission from ref. [46]. Copyright 2019, American Chemical Society.

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In iron-mediated •OH generation, Fe2+ exists much better catalytic activity than Fe3+. However, Fe2+ is unstable and easily oxidized [88]. Consequently, elevating Fe2+ content is a feasible approach to promote •OH generation. Given the effectivity of iron redox cycling, a simultaneous supply of iron ions and some reductants has been received widespread attention, such as tannic acid, EGCG and GA [4749]. These reductants are mostly polyphenolic compounds, which can chelate Fe3+ to form metal polyphenol network nanocarriers [50]. The formed nanocarriers show excellent aqueous dispersion due to the presence of phenolic hydroxyl groups. The chelation forces between polyphenol and Fe3+ can easily break in acidic conditions, resulting in the release of polyphenol and Fe3+. The released Fe3+ can be reduced into Fe2+ by polyphenol compounds, achieving Fe2+-supply-regeneration cycling [89].
As an interesting paradigm, Mu et al. designed and synthesized DOX/Fe3+/EGCG NPs using a one-pot green method. DOX, EGCG and Fe3+ could be simultaneously delivered into the tumor sites via the formed nanocarriers. After endocytosis into tumor cells, the DOX/Fe3+/EGCG NPs could be degraded and release DOX, EGCG and Fe3+ under high GSH and acidic conditions (Fig. 5). The liberated EGCG-mediated Fe2+ generation could effectively achieve Fe2+-cycling supply. The Fe2+-mediated •OH generation via the Fenton reaction could rapidly promote cancer cell death. Moreover, DOX-mediated chemotherapy could enhance the effect of tumor treatment. The experimental results demonstrated that DOX/Fe3+/EGCG NPs had a remarkable antitumor effect [51]. The therapeutic strategy provided new insights into the effective Fe2+ supply to tumor sites.
Fig.5 Schematic illustration of the synthetic process and the therapeutic mechanism of the DOX/Fe3+/EGCG NPs. Reprinted with permission from ref. [51]. Copyright 2020, American Chemical Society.

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2.2 Mn-based Fenton catalysts

The tumor microenvironment features low pH, overproduced H2O2 and a high GSH concentration. The generated •OH can be eliminated by intracellular GSH, significantly reducing the curative effects [90]. Consequently, developing a novel treatment method to enhance •OH accumulation by promoting GSH consumption and increasing •OH generation is necessary. According to literature reports, Mn-based nanomaterials could react with intracellular GSH, promoting GSH depletion and Mn2+ generation. The produced Mn2+ could catalyze H2O2 decomposition into •OH in the presence of HCO3 via the Fenton-like reaction. Therefore, Mn-based nanomaterials could induce GSH depletion and enhance •OH accumulation. Given their excellent advantages, Mn-based nanocarriers could be used as Fenton catalysts [5256,91].
As an example, Lin et al. obtained the MS@MnO2 NPs by wrapping mesoporous silica on the surface of MnO2. As depicted in Fig. 6, MnO2 was easily disintegrated by intracellular GSH, inducing GSH depletion and Mn2+ release. The GSH depletion enhanced the accumulation of Mn2+-mediated •OH generation. The results in vitro and in vivo indicated that MS@MnO2 NPs exhibited significant anticancer efficacy. This work provided a paradigm to design Fenton catalyst-based nanoagents with the ability to deplete intracellular GSH for enhanced •OH accumulation [57]. Mn-based nanocarriers as Fenton catalysts existed excellent antitumor effectiveness, which could attribute to their excellent Mn2+ delivery and GSH depletion capabilities, resulting in the •OH accumulation.
Fig.6 Schematic illustration of the mechanism of MS@MnO2 NPs for combination therapy. Reprinted with permission from ref. [57]. Copyright 2018, John Wiley and Sons.

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2.3 Cu-based Fenton catalysts

The •OH generation is not only restricted by limited catalytic ions and high content of GSH in tumor cells but also restrained by undesirable pH conditions of the Fenton reaction [92,93]. The occurrence of Fenton reaction requires a low pH (3–4). Hence, a slightly acidic tumor microenvironment can limit •OH generation, reducing antitumor effectiveness. Consequently, developing a new Fenton catalyst to generate abundant •OH in a weakly acidic condition is highly desired. Based on the published literature, Cu+ with reductive ability could react with intracellular H2O2 to generate •OH in a broad pH range [94]. However, Cu+ was unstable and prone to be oxidized into Cu2+. Thereby, Cu-based nanocarriers were generally introduced into cells in the form of Cu2+. The introduced Cu2+ could be transformed into Cu+ in the presence of GSH, which could promote GSH depletion to destroy the intracellular oxidative balance, promoting the accumulation of the generated •OH [95]. Cu-based nanomaterials were constructed to boost •OH generation such as copper-based metal-organic frameworks [58,96], copper sulfides, copper selenium [59,60], and other copper-based nanocarriers [61,62].
As an example, Ma and co-workers designed and synthesized Cu-Cys NPs through the self-assembled copper-amino acid mercaptide for GSH-activated and H2O2-reinforced •OH generation. As shown in Fig. 7, Cu-Cys NPs could react with excess intracellular GSH to induce the depletion of GSH and generation of Cu+. Subsequently, the generated Cu+ could react with endogenous H2O2 to produce highly oxidative •OH with a rapid reaction rate in the faintly acidic microenvironment, efficiently inducing apoptosis of cancer cells. The in vitro and in vivo results indicated that Cu-Cys NPs exhibited relatively high cytotoxicity to cancer cells, showing efficient tumor growth suppression [63]. The designed nanocarrier that responsive to tumor microenvironment showed potential application in •OH-mediated antitumor therapy. Cu+-mediated Fenton reaction could occur in the wide pH range to generate •OH, improving the efficiency of •OH generation and the therapeutic effect.
Fig.7 Schematic illustration of the synthetic process and the therapeutic mechanism of the Cu-Cys NPs. Reprinted with permission from ref. [63]. Copyright 2019, American Chemical Society.

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3 Elevation of H2O2 level for enhanced •OH generation

The effective •OH generation relies not only on the supply of Fenton catalysts but also on sufficient H2O2 as reaction substrates. Although H2O2 is overexpressed in tumor sites, it is still insufficient to generate considerable •OH to achieve satisfying therapeutic performance. Therefore, facilitating H2O2 production in the tumor region can address insufficient endogenous H2O2 and promote abundant •OH generation. Plentiful therapeutic strategies have been designed to increase intracellular H2O2 levels (Table 1). For instance, GOD can effectively catalyze intracellular glucose oxidation to produce gluconic acid and H2O2 [97]. Moreover, as an artificial enzyme, ultrasmall Au NPs can have specific GOD-like catalytic activity, which can also catalyze glucose oxidation to boost H2O2 generation [98,99]. Superoxide dismutase (SOD) or SOD-like enzyme can convert intracellular O2•− into H2O2, increasing H2O2 amounts [100102].
Except for the above-mentioned enzymes, Asc [103] and metal peroxides (MO2) [104,105] have been aroused attention in the ability of H2O2 elevation due to their higher stability and lower cost. Organic compounds, including CA and La, can elevate intracellular H2O2 content. Based on the mechanism of H2O2 generation, strategies for the upregulation of H2O2 levels are summarized in Fig. 8.
Fig.8 Schematic illustration of various strategies to boost H2O2 generation.

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3.1 Glucose oxidase or glucose oxidase-like enzyme-catalyzed H2O2 generation

As an endogenous oxidoreductase, GOD comprises two identical polypeptide chain subunits and flavin adenine dinucleotide coenzymes, specifically catalyzing intracellular β-D-glucose oxidation to produce gluconic acid and H2O2 in the presence of O2 and H2O [64,106109]. The therapeutic strategies based on GOD-mediated H2O2 generation have been used in cancer therapy [65,110113]. According to the catalytic mechanism, the GOD-catalyzed H2O2 generation requires the participation of O2. However, given the hypoxic characteristic of the tumor microenvironment, the efficacy of GOD-catalyzed H2O2 generation is significantly hindered. Consequently, increasing intracellular O2 content is a suitable approach to improve the efficiency of GOD-catalyzed H2O2 production.
As an example, Lin’s group synthesized multifunctional nanocarriers using Fe5C2-GOD as the core and pH-responsive MnO2 as the outer shell to form Fe5C2-GOD@MnO2 (Fig. 9). Upon entering tumor cells, the acidic microenvironment could decompose the MnO2 to generate O2, simultaneously inducing the GOD release and the Fe2+ release from Fe5C2 NPs. The generated O2 would promote GOD-catalyzed glucose oxidation to enhance H2O2 generation and decrease intracellular pH. Decreasing pH and generating H2O2 would speed up Fe2+-catalyzed •OH generation, further triggering cancer cell death. The experimental results suggested that Fe5C2-GOD@MnO2 exhibited an excellent antitumor effect due to the MnO2-mediated O2 supply and GOD-activated H2O2 production for reinforced Fe2+-mediated •OH generation [66]. The designed Fe5C2-GOD@MnO2 nanocarriers provided a potential strategy to improve tumor-specific •OH production and minimize side effects on normal tissues.
Fig.9 Schematic diagram of the therapeutic mechanism of Fe5C2-GOD@MnO2 nanocarriers. Reprinted with permission from ref. [66]. Copyright 2018, American Chemical Society.

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However, as a natural enzyme, GOD can be easily inactivated under severe conditions, restricting its application. The ultrasmall Au NPs as an artificial nanozyme have attracted attention by virtue of their specific GOD-like catalytic activity, high stability, and significant catalytic activity against harsh conditions [67,114117]. As an example, Gao et al. designed and synthesized the cascade catalytic nanoplatform by integrating 1.5 nm Au NPs and ultrasmall Fe3O4 NPs into DMSN NPs with large pore channels to construct DMSN-Au-Fe3O4 NPs. The PEG was further modified on the surface of DMSN-Au-Fe3O4 NPs to improve the stability (Fig. 10). The formed DMSN-Au-Fe3O4-PEG NPs could trigger intracellular cascade catalytic reaction under the tumor microenvironment. Au NPs as a GOD-like nanozyme could catalyze intracellular glucose oxidation to generate gluconic acid and H2O2. The decrease in pH would promote •OH generation via the Fenton reaction between ultrasmall Fe3O4 NPs and H2O2, triggering tumor cell death. Extensive evaluations in vitro and in vivo demonstrated that the DMSN-Au-Fe3O4-PEG NPs showed excellent therapeutic effects with a tumor suppression rate of 69.08% and without additional side effects [68]. Therefore, tumor microenvironment-triggered nanocarrier not only provided a “toxic-drug-free” therapeutic strategy but also stimulated the development of tumor-specific therapies.
Fig.10 Schematic illustration of the synthetic process and the therapeutic mechanism of the DMSN-Au-Fe3O4-PEG NPs. Reprinted with permission from ref. [68]. Copyright 2019, John Wiley and Sons.

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3.2 SOD or SOD-like enzyme-catalyzed H2O2 generation

Intracellular O2•− can react with H+ to form H2O2 during the catalysis of SOD [118]. Hence, SOD or SOD-like enzyme can increase the intracellular H2O2 concentration [119,120]. Inspired by this principle of H2O2 formation, Ma et al. constructed the Fe3O4@PEI-Pt(IV)-PEG (FePt-NP2) nanocarrier with a hydrodynamic size of 252 nm. As depicted in Fig. 11, once injected into cancer tissues, FePt-NP2 could be decomposed in an acidic microenvironment, liberating iron ions and Pt. The liberated Pt-mediated O2•− generation and chemotherapy could enhance antitumor efficacy. The formed O2•− could be converted into H2O2 under the catalysis of SOD. The up-regulation of H2O2 content could accelerate the •OH generation between the released iron ions and H2O2, inducing tumor cell death. The synthesized sequential drug delivery nanocarriers could achieve tumor site-specific ROS generation utilizing the supply of iron ions and the elevation of H2O2 content, enhancing anticancer effect. The in vitro and in vivo results demonstrated that FePt-NP2 showed outstanding antitumor outcomes and potential application in cancer therapy [69]. This work provided a promising delivery method for synergistic therapy. Besides SOD enzyme, the SOD-like enzyme could catalyze O2•− to form H2O2, elevating intracellular H2O2 content. For example, Sang et al. synthesized ZIF-67 NPs with SOD-like activity and Fenton-like catalytic activity. As shown in Fig. 12, the synthesized ZIF-67 could catalyze intracellular O2•− to generate H2O2. Moreover, the elevated H2O2 could be sequentially converted into •OH in the presence of ZIF-67. To improve the therapeutic effect and increase the stability, 3-AT and PEG were modified on the surface of ZIF-67 (named PZIF67-AT). On one hand, 3-AT as the CAT inhibitor could suppress H2O2 decomposition. On the other hand, PZIF67-AT-mediated GSH depletion could also prohibit H2O2 clearance [70]. The inhibition of H2O2 clearance had been proven to significantly increase •OH generation, achieving better therapeutical effects. This work provided new insights into the design of H2O2-supplementing strategies.
Fig.11 Schematic diagram of the therapeutic mechanism of FePt-NP2 for synergistic actions. Reprinted with permission from ref. [69]. Copyright 2017, American Chemical Society.

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Fig.12 Schematic representation of (a) the synthesis of PZIF67-AT NPs and (b) PZIF67-AT NPs-mediated intensive •OH production. Reprinted with permission from ref. [70]. Copyright 2020, American Chemical Society.

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3.3 Ascorbate-mediated H2O2 generation

Ascorbate (Asc) has been frequently utilized to elevate intracellular H2O2 levels. According to existing research reports, in extracellular fluid, Asc at the pharmacologic concentration could lose one electron and form Asc•−; cellular O2 could obtain an electron from Mn to form O2•−; Mn could simultaneously be reduced to Mn–1 during this process; the intracellular H+ subsequently could react with O2•− to produce H2O2 and O2 [71,121126]. Asc-mediated H2O2 generation has received great attention due to its biosafety. Based on this mechanism, An and co-workers synthesized the hybrid nanocarriers by physically encapsulating polar ferric ammonium citrate and nonpolar RSL3 into the lipid-coated calcium phosphate (CaP) core and shell, respectively. The formed nanocarrier with a suitable particle size was named CaP-Fe/RSL3. As shown in Fig. 13, the hybrid nanocarriers could be quickly degraded in an acidic environment. Asc-induced selective enrichment of H2O2 coupled with Fe3+ co-delivery could boost the •OH levels in tumor sites. Simultaneous liberation of RSL3 as a GPX4 inhibitor could result in the accumulation of lipid peroxides, enhancing treatment efficacy. The in vitro and in vivo results showed that Fe3+ delivery coupled with intraperitoneal administration of Asc had an excellent antitumor performance [72]. The combinational approach produced significantly elevated •OH levels, offering a new therapeutic method for enhancing therapeutic performance.
Fig.13 Schematic illustration of the therapeutic mechanism of CaP-Fe/RSL3+ Asc. Reprinted with permission from ref. [72]. Copyright 2019, American Chemical Society.

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3.4 Metal peroxide-mediated H2O2 generation

The above-mentioned GOD or GOD-like enzyme, SOD or SOD-like enzyme, and Asc can promote H2O2 production, but these catalytic reactions severely depend on the cellular O2 concentration [73,127129]. However, hypoxia is regarded as a major feature of cancer cells, affecting the efficiency of H2O2 generation and reducing the therapeutic effect. Therefore, developing new therapeutic methods to overcome the hypoxic environment and increase H2O2 content is of importance. MO2 are composed of O2•− and metal ions, which have been widely used to increase intracellular H2O2 content without the assistance of O2. The MO2 can be dissociated to release metal ions and O2•− in acidic conditions. The released O2•− can react with H+ to produce H2O2. The MO2-based nanocarriers have been extensively used as H2O2 generators because of their simple preparation, low cost, and high stability [74,75,130]. Based on this, Zhang et al. fabricated Fe-GA/CaO2@PCM nanocarriers with thermal responsiveness and self-sufficient H2O2 by utilizing organic PCMs to encapsulate Fe-GA NPs and ultra-small CaO2 (Fig. 14). The thermally responsive PCMs melted with the increase of temperature, inducing the release of internal Fe-GA and CaO2. The liberated CaO2-mediated self-produced H2O2 would be transformed into •OH by reacting with Fe-GA to increase •OH levels, improving the antitumor effect. In addition, the Ca2+-mediated mitochondrial damage could enhance the apoptosis of cancer cells. Due to the thermal-responsive feature, the designed Fe-GA/CaO2@PCM could specifically release the inner drugs in tumor sites, avoiding the serious damage on normal cells [76]. Thus, MO2-based nanocarriers provided a new therapeutical strategy, specifically boosting H2O2 generation to improve the efficiency of •OH generation at hypoxic conditions.
Fig.14 Schematic illustration of the synthetic process and the therapeutic mechanism of Fe-GA/CaO2@PCM. Reprinted with permission from ref. [76]. Copyright 2020, The Royal Society of Chemistry.

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3.5 CA-mediated H2O2 generation

CA as a primary active ingredient of cinnamon, has been widely used as a food additive approved by Food and Drug Administration. CA and its derivatives have been proven effective in boosting H2O2 generation, amplifying tumor H2O2 levels to increase •OH generation. Numerous strategies based on CA-mediated H2O2 generation have been used to amplify intracellular oxidative stress for triggered the death of cancer cells [77,131133]. As an example, Kwon et al. skillfully synthesized dual acid-sensitive PolyCAFe micelles, which could concurrently deliver H2O2 generator benzoyloxycinnamaldehyde (BCA) and Fenton catalyst Fc into the tumor site, escalating intracellular oxidative stress for preferentially triggered cancer cell death. As shown in Fig. 15, after entering the weakly acidic tumor microenvironment, PolyCAFe micelles would release the BCA and Fc due to the cleavage of the acid-sensitive bond. BCA-mediated H2O2 generation could elevate H2O2 levels to reinforce Fc-mediated •OH generation. The in vitro and in vivo results verified that PolyCAFe micelles existed excellent therapeutic performance and favorable biocompatibility [78]. This study provided an innovative strategy for exploiting new therapeutic nanoplatforms, simultaneously amplifying tumor H2O2 levels and enhancing •OH generation for specifically triggered cancer cell death with remarkable biosafety.
Fig.15 Schematic diagram of the PolyCAFe-triggered cancer apoptosis via boosting H2O2 generation and •OH generation. Reprinted with permission from ref. [78]. Copyright 2016, American Chemical Society.

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3.6 La-mediated H2O2 generation

La as a special H2O2-producing agent could generate O2•− and H2O2. After entering cancer cells, La can selectively increase the content of H2O2 in tumor sites under the action of overexpressed quinone oxidoreductase 1 (NQO1). La-mediated H2O2 generation has been reported and used to improve therapeutical performance in cancers [7981]. As a paradigm, Li et al. constructed the self-supply H2O2 nanoplatform via loading La into Fe@Fe3O4@Cu2–xS-PEG to form Fe@Fe3O4@Cu2–xS@La-PEG. As depicted in Fig. 16, La released from Fe@Fe3O4@Cu2–xS@La-PEG could selectively boost tumor site-specific H2O2 generation under the catalysis of NQO1. Subsequently, the iron and copper ions released from the Fe@Fe3O4@Cu2–xS in the acidic environment could convert H2O2 into highly toxic •OH via Fenton reactions, dramatically improving •OH generation with minimal systemic toxicity due to low NQO1 expression in normal tissues. The in vivo results demonstrated that the Fe@Fe3O4@Cu2–xS@La-PEG significantly inhibited tumor growth [82]. The therapeutical strategy based on La-mediated H2O2 generation provided new insight into the enhancement of tumor-selective •OH generation, significantly promoting NQO1-overexpressing tumor-cell apoptosis with minimal side effects on normal cells.
Fig.16 Illustration of the synthetic process and therapeutic mechanism of Fe@Fe3O4@Cu2–xS@La-PEG. Reprinted with permission from ref. [82]. Copyright 2020, American Chemical Society.

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4 Conclusions and prospect

The •OH production is generally considered as H2O2 decomposition in the presence of Fenton catalysts via Fenton or Fenton-like reactions. The generated •OH can induce tumor cell death by attacking and oxidizing intracellular biomolecules, such as DNA, proteins, and polyunsaturated fatty acids. However, the efficacy of •OH generation is severely hindered by insufficient intracellular H2O2 contents and limited Fenton catalysts. Therefore, various strategies have been widely used to improve •OH generation. This review mainly summarizes current developments of hydroxyl radical-based cancer therapy, including effective supply of typical metal-based Fenton catalysts and up-regulation of H2O2 levels in tumor sites. These strategies remarkably enhance the efficacy of •OH generation, increasing the therapeutic performance.
However, the hydroxyl radical-based cancer therapy still exists the following four problems that need to be further studied and optimized. 1) The excess metal ions introduced into cells can cause severe damages to human health and limit further clinical translation. Therefore, detecting or controlling the amount of metal ion introduction is an effective strategy to avoid damage on normal cells or tissues. 2) The nanocarriers that are used to deliver Fenton catalysts lack tumor-specific target, which may cause damage on normal cells with adverse effects. Consequently, exploiting tumor-target nanocarriers to specifically target tumor cells is an effective strategy to solve this problem. 3) The •OH generation via the Fenton reaction needs low pH conditions, ranging from 2 to 4. However, the pH of the tumor microenvironment predominantly ranges from 6.5 to 7, the pH of endosomes is approximately 5.0, and the pH of lysosomes is about 4.5. Therefore, decreasing the pH of the tumor microenvironment or delivering nanocarriers to endosomes or lysosomes is an effective approach to enhance the efficiency of •OH generation. 4) GSH serves as an important antioxidant substance, eliminating the generated ROS to maintain intracellular redox balance. Compared with normal tissues, tumor tissues are mainly characterized by higher GSH content (2 to 10 mmol·L−1). The therapeutic efficiency of •OH-based cancer therapy will be limited because of GSH elimination. Therefore, simultaneously promoting intracellular GSH depletion and increasing ROS generation will enhance the efficiency of •OH generation. Although there are still some problems required to be further solved and optimized, hydroxyl radical-involved cancer therapy shows high prospect.

Acknowledgments

The authors acknowledge the financial support from the Tianjin Science and Technology Committee (Grant No. 19JCYBJC28400), the Basic Research General Program of Shenzhen Science and Technology Innovation Commission in 2020 (Grant No. JCYJ20190806162412752).
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