Hydroxyl radical-involved cancer therapy via Fenton reactions

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.

Key words： hydroxyl radical; Fenton catalyst; hydrogen peroxide; cancer therapy

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 [14–16]. 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 [19–22].

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 [23–26]. 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 [27–33].

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 [83–85]. 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 [40–45,87]. 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 [47–49]. 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 [52–56,91].

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 [100–102].

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 [64,106–109]. The therapeutic strategies based on GOD-mediated H₂O₂ generation have been used in cancer therapy [65,110–113]. 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 [67,114–117]. 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 M^n–1 during this process; the intracellular H⁺ subsequently could react with O₂^•− to produce H₂O₂ and O₂ [71,121–126]. 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 [73,127–129]. 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 [77,131–133]. 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 [79–81]. As a paradigm, Li et al. constructed the self-supply H₂O₂ nanoplatform via loading La into Fe@Fe₃O₄@Cu_2–xS-PEG to form Fe@Fe₃O₄@Cu_2–xS@La-PEG. As depicted in Fig. 16, La released from Fe@Fe₃O₄@Cu_2–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@Cu_2–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@Cu_2–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@Cu_2–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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