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Accepted Article

Title: Chemodynamic Therapy: Tumour Microenvironment-Mediated

Fenton and Fenton-like Reaction

Authors: Zhongmin Tang, Yanyan Liu, Mingyuan He, and Wenbo Bu

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Angewandte Chemie International Edition 10.1002/anie.201805664

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Chemodynamic Therapy: Tumour Microenvironment-Mediated

Fenton and Fenton-like Reaction
Zhongmin Tang,[a,b] Yanyan Liu,[c] Mingyuan He,[c] Wenbo Bu*[a,c]

Accepted Manuscript

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Angewandte Chemie International Edition
MINIREVIEW
Abstract: Tailored to the specific tumour microenvironment,
which involves acidity and the overproduction of hydrogen
peroxide, advanced nanotechnology has been introduced to
generate the hydroxyl radical (•OH) primarily for tumour
chemodynamic therapy (CDT) via the Fenton reaction and
Fenton-like reaction. Numerous studies have investigated the
enhancement of CDT efficiency, primarily the increase in the
amount of •OH generated. Notably, various strategies based on
the Fenton reaction have been employed to enhance •OH
generation, including nanomaterials selection, modulation of the
reaction environment and external energy fields stimulation,
which are discussed systematically in this minireview.
Furthermore, the potential challenges and the methods used to
facilitate CDT effectiveness are also presented to support this
cutting-edge research area.
1. Introduction
The Fenton reaction, which is simply defined as the
generation of highly oxidative hydroxyl radicals (•OH) from
hydrogen peroxide (H2O2), is catalysed by ferrous ion (Fe2+) and
has been widely used to remove refractory organics.[1-3] After
extensive research, advanced nanotechnology has created a
broad stage for the further development and extension of the
Fenton reaction, such as iron-based nanomaterials for the
Fenton reaction and Fenton-like reaction,[4,5] other metal-based
nanomaterials, and graphene oxide for the Fenton-like
reaction.[6-8] However, a major issue encountered by scientists is
how to broaden the applications of the Fenton reaction and
Fenton-like reaction, which would also provide possibilities and
has prompted many studies in other fields in addition to the
ecological environmental field. Characterized by mild acidity,[9]
H2O2 overproduction,[10] low catalase activity[11] and hypoxia,[12]
the tumour microenvironment (TME) not only provides a suitable
environment and nutrition for tumour development[13] and
metastasis[14,15] but also furnishes the "gate" for selective and
efficient tumour treatments. In this case, numerous TME-
responsive nanomaterials have been developed in recent
decades, the majority of which are TME-responsive drug
delivery nanocarriers[16-18] that have deficiencies, such as
insufficient drug loading and easy leakage to damage normal
tissues. Moreover, studies focusing on current clinical
treatments would provide researchers with effective guidance to
[a] Dr. Z. Tang and Prof. W. Bu
State Key Laboratory of High Performance Ceramics and Superfine
Microstructure, Shanghai Institute of Ceramics, Chinese Academy of
Sciences, Shanghai 200050, P.R. China
E-mail: wbbu@mail.sic.ac.cn
[b] Dr. Z. Tang
University of Chinese Academy of Sciences, Beijing 100049, P.R.
China.
[c] Dr. Y. Liu, Prof. M. He, and Prof. W. Bu
Shanghai Key Laboratory of Green Chemistry and Chemical
Processes, School of Chemistry and Molecular Engineering, East
China Normal University, Shanghai 200062, P.R. China
E-mail: wbbu@chem.ecnu.edu.cn;
This article is protected by copyright. All rights reserved.
10.1002/anie.201805664
explore more suitable new therapies. For example, radiotherapy
generates reactive oxygen species (ROS)[19] in the tumour area
through X-rays to destroy the tumour. Certain chemotherapeutic
drugs, such as tirapazamine (TPZ)[20,21] and doxorubicin
(DOX),[22] also generate ROS to fight tumours. In addition, the
drug artemisinin is a highly effective treatment for malaria. One
of the principles underlying the effects of this drug is that the iron
in the residual haeme observed in patients with malaria induces
the decomposition of artemisinin by catalysing the formation of a
peroxide bridge to produce hydroxy radicals,[23,24] which are
highly active and lethal, subsequently eliminating the malaria
parasite. Chemists quickly linked this mechanism to the classical
Fenton reaction.
Accepted Manuscript
After considering these different fields, chemodynamic therapy
(CDT), an emerging therapeutic strategy, was recently proposed
by our group[25] and defined as in situ treatments using the
Fenton reaction or Fenton-like reaction to generate ·OH in
tumour sites. Briefly, iron-based nanomaterials dissolve ferrous
ions under the mildly acidic conditions of the TME and initiate
the Fenton reaction to overproduce H2O2, generating •OH to
trigger apoptosis and inhibit the tumour. Most importantly, this
approach ensures normal tissue safety in some degree,
because the Fenton reaction is substantially suppressed under
the slight alkaline conditions and in the presence of insufficient
H2O2 in a normal microenvironment.[26] Even so, the potential
toxicities of nanomaterials should be taken into consideration for
further applications. This strategy not only broadens the
applications of the Fenton reaction but also simplifies its
potential for clinical translation. Compared with chemotherapy,
radiotherapy, photothermal therapy and photodynamic therapy,
CDT has the following advantages: i) highly logical and selective,
ii) and activated by endogenous stimulus. Meanwhile, we could
also find the connections between CDT and current following
clinical cases except for the malaria treatment using artemisinin:
The antitumor principle of bleomycin[27a, 27b] is that the bleomycin
is firstly embedded in DNA, and then the complex of bleomycin
with iron would generate superoxide and hydroxyl radicals to
break DNA strand. At the same time, the cardiotoxicity of
anthracycline drugs is mainly from the reactive oxygen species,
especially hydroxyl radicals, generated by the binding iron ions
with H2O2,[27c] which also provides enlightment for CDT.
Therefore, studies aimed at the further development of CDT
have flourished, which supports the potential utility of CDT for
clinical translation.
Since the development of CDT, the selection of suitable
nanomaterials, the modulation of the reaction environment
(reduced pH levels, increased amounts of reactants and
decreased amounts of glutathione) and the assistance of an
exogenous energy field have been used to optimize the effect of
CDT, which relies on the guidance of the Fenton or Fenton-like
reactions and basic chemical principles. Although the majority of
the existing CDT agents are iron-based inorganic nanomaterials,
other inorganic nanomaterials and organic nanomaterials have
also been used to enrich the library. Moreover, nanomaterials
used for CDT without low pH dependence are also satisfactory
choices. Nanomaterials have the ability to exclusively produce
protons or H2O2 in tumours should also be taken into
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MINIREVIEW

consideration. Above all, the selection of nanomaterials should 2. Nanomaterials selection

consider the following issues: more functionality and easy
synthesis procedures, which are crucial for the application in the Due to the irreplaceable role of the catalyst in the Fenton
real world.[28] In addition, the efficiency of CDT could also be reaction and Fenton-like reaction, the selection of nanomaterials
improved by the consumption of reducing substances in the (iron-based inorganic materials, other metal-based inorganic
TME, such as glutathione (GSH), or the modulation of H+ and materials or metal-organic framework nanomaterials) is very
H2O2 levels by regulating gene expression. Fortunately, several important.
other external energy fields, such as light, heat, sonification,
electricity or magnetic fields, are desirable to promote the
Fenton-like reaction. In summary, the purpose of this minireview
is not merely to concentrate on the recent important findings 2.1. Iron-based inorganic nanomaterials
related to CDT, but also to provide rational instructions to exploit
other tumour treatments. The first step in increasing the CDT efficiency is to increase

Zhong Min Tang graduated from Shandong
University with a B.E. in Materials Science
and Engineering in 2014. He is now pursing
his Ph.D. under the supervision of Prof.
Wenbo Bu at Shanghai Institute of Ceramics,
Chinese Academy of Sciences (SICCAS).
Currently, his research is focused on tumour
microenvironment-sensitive nanoplatforms
for diagnosis/therapeutic systems.
Yan Yan Liu received her Ph.D. degree from
SICCAS. She is now a lecturer at East China
Normal University (ECNU). Her research is
focused on the design and
multifunctional nanomaterials for biomedical
applications
Accepted Manuscript
the catalyst ion amount. The method should closely linked with
the TME, such as the acidity level, which is created by the
generation of large amounts of lactic acid resulting from the
upregulation of glycolytic metabolism.[29] For instance, our group
synthesized amorphous Fe0 nanoparticles (AFeNPs) (Figure
1a),[25] which were rapidly ionized in an acidic TME to release
more Fe2+ ions than Fe0 nanocrystals (FeNCs) for CDT, because
it had the reactive nature of metallic glasses. As presented in
Figure 1b and Figure 1c, the release rate of ferrous ions from
the AFeNPs reached 57% at a pH of 6.5 and 100% at a pH of
5.4 within 6 h, which were much higher than those observed for
the FeNCs. Moreover, both AFeNPs and FeNCs tended to
slowly release ferrous ions at a neutral pH. These results
confirmed the capacity of AFeNPs for selective ferrous ion
release, thus ensuring the efficiency of CDT. In addition, many
other iron-based nanomaterials, including Fe oxides,[30-32]
synthesis [FeO(OH)n][33] and M(Sn,Mn)Fe2O4[34,35] have also been
introduced as CDT agents, but none have focused on increasing
the release of the catalytic Fe2+ ions.

Ming Yuan He, Chinese Academician of

Sciences, is a chemistry professor at ECNU.
His research areas are catalytic materials
and petrochemical catalysts. He has
published over 200 scientific papers and has
submitted more than 200 domestic and
foreign patents, over 150 of which have been
authorized.

Wen Bo Bu received his Ph.D. degree from

Nanjing University of Technology. He is a full
professor at ECNU and an adjunct professor
at SICCAS. His current research interests
include the design and synthesis of
multifunctional nanomaterials for further
cancer imaging and therapeutic applications.

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Angewandte Chemie International Edition 10.1002/anie.201805664

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Accepted Manuscript
Figure 1. (a) Preparation of AFeNPs. (b and c) Time-dependent ion release from FeNCs and AFeNPs at different pH values. Reproduced with permission
from ref. [25]. Copyright 2016. Wiley-VCH. (d) The mechanism underlying the effects of MnO2 as an enhanced CDT agent for cancer. (e) UV/Vis absorption
spectra and photo (inset) of methylene blue (MB) after degradation by the Mn2+-mediated Fenton-like reaction in different solutions. (f) MB degradation of
different groups. (g) Bar graph showing the percentage of MB degradation in various groups. Reproduced with permission from ref. [38]. Copyright 2018,
Wiley-VCH.

2.2. Other metal-based inorganic nanomaterials

Although the TME exhibits the characteristics of a low pH and

hydrogen peroxide overproduction, it also has a higher
concentration of GSH than normal tissues,[36] which consumes
the generated hydroxyl radicals, thereby limiting the CDT effect.
In addition to the catalytic effect of ferrous ions, other transition
metal ions, including Mn2+, Ti3+, Cu2+ and Co2+ ions, could also
act as catalytic ions.[37] From this perspective, the combination of
the GSH consumption with increasing catalyst ion generation in
one nanomaterial is both a challenge and a potential application.
For example, Lin et al. prepared a CDT agent, MnO2-coated MS
NPs (MS@MnO2 NPs), which combined the ·OH generation and
GSH depletion.[38] As depicted in Figure 1d, the MnO2 shell
reacted with GSH to produce Mn2+ and glutathione disulphide
(GSSG) and subsequently triggers ·OH generation from H2O2 in
the presence of HCO3-/CO2. The efficiency of ·OH generation
was investigated by monitoring methylene blue (MB)
degradation. Compared with the group treated with H2O2 and Figure 2. (a) Schematic illustrating the preparation of MON-p53. (b)
Schematic illustrating MON-p53-mediated anticancer therapy (c) Viability of
MnCl2 in aqueous solution, apparent degradation of MB was
HT1080 cells treated using different metal−organic networks coated with
detected after a 30 min incubation in NaHCO3/CO2 buffer, which PEI/p53 and erastin with metal ions. (d) Curves showing HT1080 tumour
confirmed the indispensable role of HCO3-/CO2 (Figure 1e). In volumes in mice during the first 25 days of treatment. Reproduced with
addition, MS@MnO2 NPs still exhibited sufficient MB permission from ref. [40]. Copyright 2016, American Chemical Society.
degradation in the presence of a high concentration of GSH of nanoparticles (the assembly of small molecules and does not
10 mM (Figure 1f and 1g), which was approximately 1.3 times have the periodic network structure) also have the potential to
higher than the concentration of free Mn2+, suggesting that be utilized for CDT. Compared with stable inorganic
MS@MnO2 NPs increased the efficiency of CDT. Therefore, the nanomaterials, MOF and macromolecular nanomaterials have
combination of other metal ions with the TME is a promising been designed for therapies or imaging[39] because of their
approach for improving CDT efficiency. flexibility and better responsiveness. Zheng et al. synthesized a
metal-organic network (MON)-p53 with a core-shell structure
2.3. Metal-organic framework nanomaterials based on a MOF, and the resulting network resulted from the
coordination between Fe3+ and tannic acid (Figure 2a).[40] In the
In addition to inorganic nanomaterials, nanomaterials with a system, ferric ions generated ·OH, and the expression of p53
metal-organic framework (MOF) and macromolecular

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Angewandte Chemie International Edition
MINIREVIEW
Figure 3. (a) Schematic illustrating the synthetic procedure used to prepare rMOF-FA. (b) Schematic showing the mechanism underlying the therapeutic
effects of rMOF-FA nanoparticles on cancer cells. (c) Iron ion release from rMOF-FA in buffers with different pH values (5 and 7.4). Reproduced with
permission from ref. [41]. Copyright 2017, American Chemical Society
protein inhibited the expression of the SLC7A11 protein
expression, thereby inducing GSH depletion to further enhance
the ·OH yield (Figure 2b). Various metal ions (Fe2+, Fe3+, Al3+,
Co2+, Ni2+, Cu2+, Mn2+ and Ca2+) had been introduced to evaluate
the cytotoxicity towards HT1080 cells, and significant
cytotoxicities were detected in cells co-incubated with MON-p53
and Fe2+ and Fe3+, confirming that the MON-p53-induced cell
death was mediated by an iron-dependent mechanism (Figure
2c). Furthermore, the shell p53 protein exhibited the ability to
regulate the SLC7A11 level and block GSH synthesis, which
ultimately enhanced the CDT efficiency in vivo, as evidenced by
the changes in the tumour volumes of different groups (Figure
2d). In addition, Burachaloo et al. fabricated a reduced iron MOF
conjugated with folic acid (rMOF-FA) as the CDT agent[41]
(Figure 3a). The MOF was unstable in an acidic environment
and rapidly released iron ions for CDT, while it was stable at
neutral pH (Figure 3b). As shown in Figure 3c, the rMOF-FA
released approximately 100% of the iron ions at pH 5.0
compared with the negligible release observed at neutral pH,
consistent with the well responsiveness and specificity of
amorphous iron nanomaterials. Other advantages of MOF, such
as the high porosity and large surface area could also been
utilized for promoting CDT efficiency.
3. Modulation of the reaction environment
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10.1002/anie.201805664
Accepted Manuscript
The Fenton reaction is affected not only by the catalytic ions
amount but also by the reaction environment, including the pH
and the amount of hydrogen peroxide or GSH. Recently, several
studies focused on modulating the reaction environment
(reducing the pH, generating more H2O2 and decreasing the
GSH amount) for CDT have emerged and presented potential
applications, which promotes researchers to develop additional
methods to optimize the treatment effect.
3.1. Reducing pH levels
For the Fenton reaction, the optimal reaction pH ranges from
2-4[42] because of the following reasons: i) it inhibits the
precipitation of ferrous and iron ions in a low pH environment;
and ii) in addition, hydrogen peroxide would be degraded under
extremely low pH conditions. For tumours, the pH of the TME
predominantly ranges from 6.5 to 7, the endosomes of tumour
cells have a pH of approximately 5.0 and lysosomes have a pH
of approximately 4.5.[43] For most materials, the number of
catalytic ions released is limited primarily by the requirement for
a weakly acidic environment, and the Fenton reaction is also
inhibited in a weakly acidic environment. Therefore, reducing the
pH of TME or delivering the nanomaterials to the nucleus or
lysosomes might also enhance the CDT efficiency.
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Accepted Manuscript
Figure 4. (a) Illustration of the synthesis and (b) multiple functions of AIO RNAi NPs. (c) Tissue penetration of AIO NPs (upper panel) and polymer NPs
(lower panel) loaded with Cy5.5-siRNA in a 3D spheroid model after a 4 h incubation. (d) Western blot and (e) immunofluorescence staining for MCT4 in PC3
cells treated with NP (siControl) or NP-(siMCT4). (f) ROS production in PC3 cells treated with or without the MCT4 siRNA. (g) Representative photos of
tumour-bearing mice and tumour tissues from various groups. Reproduced with permission from ref. [44]. Copyright 2018. Wiley-VCH.

Liu et al. developed an amorphous iron oxide (AIO) RNAi NP
nanoplatform (Figure 4a),[44] The siRNA was encapsulated
within NPs to limit enzymatic contact, degradation and burst
release during circulation in the blood, and the small size of the
NPs permitted it to deeply penetrate tumour tissues. This novel
strategy was summarized as an initial blockade of intracellular
lactate/H+ production via MCT4 silencing to induce cell acidosis
and the subsequent release of large amounts of iron ions to
react with more H2O2 molecules, which was also stimulated by
the intracellular lactate efflux block, as depicted in Figure 4b. As
shown in Figure 4c, AIO NPs penetrated greater depths of the
tumour than polymer NPs loaded with Cy5.5-siRNA, thus
potentially extending the treatment area to enhance CDT
efficiency. Moreover, the expression of MCT4 analysed by
western blotting and immunofluorescence staining (Figure 4d
and 4e) confirmed the silencing effect of AIO NPs. The
intracellular H2O2 concentration was substantially increased after
silencing in PC3 cells, which resulted from intracellular lactate
accumulation (Figure 4f). Similarly, MCT4 expression was also
inhibited, and the AIO NPs exhibited sufficient inhibition on
tumour growth in vivo (Figure 4g).
3.2. Increasing the H2O2 level and decreasing the GSH level
The concentration of H2O2 in tumour cells is up to 100 µM,
while it is just 20 nM in normal tissues.[26] However, the amount
in tumour cells is still low to serve as an efficient CDT. The
strategy of inhibiting MCT4 expression using the (AIO) RNAi NP
nanoplatform not only reduces the pH but also increases H2O2
generation. Additionally, Wang et al. also constructed integrated
multifunctional polymeric nanoparticles for tumour therapy.[45]
The micelles had cores formed by L-ascorbyl palmitate (PA) and
ferrocenecarboxylic acid hexadecyl ester (DFc) (Figure 5a) and
poly(ethylene glycol) (PEG) shells, which were linked via the
host-guest interaction. Responding to the pharmacological
concentration of ascorbic acid, the nanoparticles promoted H2O2
generation, and the Fc groups subsequently suppressed tumour
growth (Figure 5b). The hydroxyl radicals were then monitored
by detecting the fluorescence intensity at a wavelength of 425
nm of 2-hydroxyterephthalic disodium, which was the product of
the reaction between disodium terephthalate and hydroxyl
radicals. Excitingly, Figure 5c showed the large increase in the
fluorescence intensity of PA/Fc-micelles after 3 h compared with
the nearly unchanged fluorescence intensity of PA and DFc
alone, which confirmed the sufficient generation of ·OH.
Meanwhile, comet assays of different groups (Figure 5d) were
conducted to reveal the degree of DNA damage, which also
revealed the efficient treatment effect of PA/Fc-Micelles (Figure
5e). In addition to the use of MnO2,[38] the strategy of introducing
RNA to modulate the amount of H2O2 production is also suitable
for decreasing the amount of GSH.
Huo et al. fused natural glucose oxidase (GOD) with
biodegradable dendritic mesoporous silica (DMS) nanoparticles
and ultrasmall Fe3O4 nanoparticles into one system for tumour
ablation.[46] GOD served as the enzyme that reacted with
glucose in the tumour area to generate H2O2 and DMS released
Fe3O4 to initiate a Fenton-like reaction, generating amounts
of ·OH (Figure 6a). Furthermore, the anticancer ability of GFD
NCs at the cellular level was evaluated using a calcein-AM/PI
probe, and the confocal laser scanning microscope (CLSM)
images showed well CDT effect on 4T1 cells (Figure 6b). The
blood glucose levels decreased 30 min after the injection of the
nanoplatform and recovered 1 h after the injection (Figure 6c),
which indicated glucose consumption by GOD. Nevertheless,
several issues remain to be resolved. First, the glucose
consumption process also requires oxygen, but the TME is
relatively hypoxic, which would inhibit the generation of H2O2. In
addition, a lack of GOD targeting to the TME would also enable
this enzyme to react with glucose in normal tissues, reducing the
selectivity of the reaction.

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MINIREVIEW

Accepted Manuscript
Figure 5. (a) Synthesis of PA/Fc-micelles. (b) Schematic illustrating the application of polymeric micelles for cancer therapy using Fenton reactions. (c)
Changes in the fluorescence intensity of 2-hydroxyterephthalic acid recorded at a wavelength of 425 nm over time after an incubation with three groups in 10%
serum-containing medium. Mean ± s.d. (n = 3). (d) Results of the comet assay using 4T1 cells and MCF-7 cells treated with various agents. Scale bars: 100
μm. (e) DNA damage in different groups, as determined from the ratio of the comet tail. Mean ± s.d. (n = 10), **p < 0.01, ***p < 0.001 (t-test). Reproduced with
permission from ref. [45]. Copyright 2018, American Chemical Society.

as well as an adjustable spot area. Moreover, the relatively low

4. Stimulation by external energy fields
Despite the limitations of external energy fields, such as an
insufficient penetration depth of light and heat radiation in
normal tissues, external energy fields (e.g., light, heat,
ultrasound, magnetic fields and electric fields) are more feasible
for development as auxiliary treatments to speed up Fenton
reaction and Fenton-like reaction to improve CDT effects.
4.1. Light stimulation to speed up Fenton reaction
As a commonly used external stimulus, light possesses the
unique characteristics of a controllable wavelength and intensity,
cost, availability and noninvasiveness also make light stimulation
more appealing. Many studies have examined tumour imaging
and therapies using light-triggered nanomaterials, such as
photoacoustic imaging, upconversion fluorescence imaging,
photothermal therapy (PTT), photodynamic therapy (PDT) and
light-responsive drug release for chemotherapy.[47] Ultraviolet
(UV) light promotes the Fenton reaction, which is recognized as
a photo Fenton reaction. Thus, the participation of UV light
would also enhance CDT efficiency. Due to the damage to
normal tissues and the extremely low penetration depth of UV
light, near-infrared light (NIR) is typically combined with
upconversion nanomaterials (UCNPs) as UCNPs could convert
NIR into UV/Vis,[48] which has also been applied frequently in
nanomedicine.

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MINIREVIEW

Accepted Manuscript
Figure 6. (a) Procedures used to synthesize Fe3O4@DMSN nanocatalysts and GOD-Fe3O4@DMSN nanocatalysts. Schematic showing the sequential
catalytic-therapeutic mechanism by which GFD NCs generate hydroxyl radicals for cancer therapy. (b) CLSM images of the distributions of viable and dead
cells stained with calcein-AM/PI after a co-incubation with various concentrations of GFD NCs at pH 7.4 and pH 6.0 for 4 h. (c) Blood glucose level in mice
at different times of day. Mean ± s.d. (n = 3). Reproduced with permission from ref. [46]. Copyright 2017, Nature.

Based on the above considerations, our group developed a
nanoplatform, NaYF4:Yb3+,Tm3+@NaYF4@dSiO2@mSiO2-
2+ 2+
Ru /Fe (UCSRF), featuring mitochondrial DNA targeting that
generates ROS via an NIR-triggered photo Fenton reaction.[49]
As shown in Figure 7a, the UCNP cores converted NIR to
UV/Vis, and the mesoporous silica shell loaded and delivered
the Fenton agent and Ru2+ complex on the surface to bind the
mitochondrial DNA. When irradiated with NIR, the
generated ·OH would destroy the mitochondrial DNA. The bio-
TEM image with the corresponding energy dispersive spectrum
(EDS) (Figure 7b) and the CLSM (Figure 7c) images all clearly
proved that the mitochondria were the preferred cellular target of
UCSRF. Compared with the phosphate buffer saline (PBS)
control, PBS with NIR irradiation, UCS-Ru2+/Fe2+ alone, UCS-
TPP/Fe2+ with NIR irradiation and UCS-Ru2+/Fe2+ with UV
irradiation groups, the UCS-Ru2+/Fe2+ with NIR irradiation group
exhibited the strongest green fluorescence, indicating the
highest level of ·OH generation (Figure 7d), consistent with the
MTT results (Figure 7e). Moreover, tumour growth was inhibited
in the UCSRF-treated group (Figure 7f and 7g). Although the
study did not directly utilize NIR light, it provided the foundation
of introducing NIR to enhance the CDT efficiency .
4.2 Heat stimulation to speed up Fenton reaction

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Accepted Manuscript
Figure 7. (a) Schematic illustrating the procedures used to synthesize UCSRF and a mitochondrial DNA-targeted and NIR-initiated photochemical therapy
(PCT) for cancer. (b) Bio-TEM image of UCSRF in cellular mitochondria. (c) Confocal images and the quantification of fluorescent intensity of the line
scanning profiles of HepG2 cells treated with different nanomaterials. (d) CLSM images of HepG2 cells from various groups reveal the generation of ·OH
using DCFH-DA as the probe. (e) In vitro viability of HepG2 cells undergoing apoptosis in response to different treatments (**p < 0.01 and ***P < 0.001). (f)
Relative tumour volumes in groups receiving different treatments for 12 days. (g) H&E staining of the tumour tissue sections from different groups of mice 3
days after NIR irradiation. Reproduced with permission from ref. [49]. Copyright 2017, Elsevier.

As another external energy field, heat has also been reported
to promote CDT using FeS2-PEG nanoparticles (Figure 8a).[50]
The synthesized FeS2-PEG nanoparticles generated localized
heat in a photothermal conversion process using an NIR laser.
Subsequently, the heat accelerated and enhanced the Fenton
reaction for amplified CDT. Figure 8b showed the electron
paramagnetic resonance (EPR) spectra and the results
obviously revealed the ability of heat to promote the Fenton
reaction. Moreover, the FeS2-PEG nanoparticles exhibited
sufficient performance in MB decolourization (Figure 8c), as the
degradation ratio improved when heat was introduced. The
imaged captured after the administration of different treatments
shown in Figure 8d revealed that the FeS2-PEG nanoparticles
substantially suppressed tumour growth after NIR irradiation,
which was ascribed to the synergistic effect of PTT and heat-
enhanced CDT. Although heat was generated indirectly via NIR
laser radiation, the results still provided evidence for the ability of
heat to enhance CDT and propel interests of developing other
heat-enhanced CDT nanomaterials.
5. Conclusions and outlook
The side effects of traditional chemotherapy and radiotherapy
technology on patients cannot be ignored. Therefore, many
researchers have focused on combining these treatments with
nanotechnology and developed novel treatment methods. Under
the direction of this pursuit, CDT has emerged as a new “green”
treatment displaying selectivity and specificity, and represents a
further development of the mechanism of chemotherapy and
radiotherapy. More importantly, CDT combines the TME and
classical Fenton reaction or Fenton-like reaction and then
destroys the tumour in situ, holding potential for clinical
translation. To date, many studies have reported new
nanomaterials that regulate the Fenton reaction in a particular
environment and use external energy fields, all of which have
promoted the development of CDT nanoagents in biomedicine.
This minireview summarizes the current development of the
field of CDT (in situ treatments using the Fenton reaction or
Fenton-like reactions to generate ·OH in tumour sites), including
the selection of nanomaterials, the regulation of the reaction
environment, and the introduction of an external energy fields as
stimulus (including light, heat, etc.) to improve the CDT
efficiency. These strategies are all based on the principle of CDT
and are discussed in depth, with an emphasis on the design and
implementation of the ideas. Nevertheless, CDT is still in its
infancy. Additional studies are required before CDT is ready for
clinical translation, as some important scientific issues must be
considered. Representative issues are listed below.

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Figure 8. (a) Schematic of the FeS2-PEG-mediated self-enhanced MRI and CDT/PTT. (b) EPR spectra obtained using the 5,5-dimethyl-L-pyrroline N-oxide
(DMPO) as the spin trap after different treatments. (c) Decolourized MB data from different groups. (d) Representative images of Balb/c mice with bilateral
4T1 tumour xenografts captured at different times after treatment. Reproduced with permission from ref. [50]. Copyright 2017, Wiley-VCH.
First, in-depth explorations of the anticancer pathways of
CDT using genetic and molecular methodologies are required
for further CDT optimization. Second, the specificity or
biocompatibility of CDT must be improved to prevent potential
damage to normal cells, because the pH of lysosomes in normal
cells is also low and would promote ·OH generation, even if the
concentration of hydrogen peroxide is very low. Third, the
targeting efficiency of CDT agents for tumour tissues should be
improved and it is a common challenge for all nanoagents.
Moreover, unified diagnostic and treatment guidelines for
different diseases should be developed. [51] Thus, it is urgent to
introduce advanced diagnostic methods (such as computed
tomography imaging, magnetic resonance imaging or positron
emission computed tomography imaging) to achieve real-time
monitoring and an assessment of CDT effect. Finally, the most
crucial issue is to increase the ·OH amount in situ in the tumour
area during the CDT process. Several feasible strategies have
been proposed as responses to these challenges and the details
are presented below. Last but not the least, the development of
nanomaterials should considers both the functionality and easy
synthesis procedures as we want to apply them in the real world.
The fields of catalysis and environmental protection might be
the source of guidelines for the selection of nanomaterials, as
certain polyoxometalates (POMs)[52] serve as pH-independent
agents that induce Fenton-like reactions. In addition, MOFs
provide extensive choices for CDT such as selecting suitable
Fe3+ MOFs for magnetic resonance contrast agents[53] when
playing roles in CDT and the surface of iron-based MOFs could
be easily functionalized for demand CDT.[54]
Second, we may increase lactic acid accumulation by
inhibiting aerobic glycolysis using strategies that reduce the
oxygen content in tumour to reduce the TME pH. Furthermore,
metal-based peroxides, which are acid-sensitive agents, should
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10.1002/anie.201805664
Accepted Manuscript
be considered to substantially increase the amount of H2O2 for
efficient CDT. With the introduction of an external light field,
UCNPs will facilitate the generation of ·OH of CDT agents, as it
could convert NIR to UV to promote Fenton-like reactions.
Moreover, MOFs could also be used for assistant
phototherapy[55] when act as CDT agents under light irradiation.
A magnetic field has been shown to stimulate heat production
from magnetic nanomaterials and indirectly enhance CDT
efficiency. Some unstable molecules containing peroxy bridges
also produce H2O2 under sonication to enhance the ·OH
production during CDT. CDT would also adequately exert its
potential when applied in combination with clinical
radiofrequency ablation technology, which utilizes an electric
field to produce hyperthermia. In summary, CDT is a flourishing
research frontier that requires further exploitation, despite the
presence of several unresolved issues. Finally, our hope is to
pursue and design optimal nanomedicines with on-demand CDT
efficiency combined with advanced diagnostic methods to
provide specific, efficient and safe protocols for treating cancer
or other diseases and improving patient health.
Acknowledgements
We gratefully acknowledge support from the National Funds for
Distinguished Young Scientists (Grant No. 51725202), the
National Science Foundation for the Young Scientists of China
(Grant No. 51702211), and the Shanghai Excellent Academic
Leaders Program (Grant No. 16XD1404000).
Angewandte Chemie International Edition 10.1002/anie.201805664

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Angewandte Chemie International Edition 10.1002/anie.201805664

MINIREVIEW
Entry for the Table of Contents (Please choose one layout)

REVIEW
Recent rapid developments in Zhongmin Tang, Yanyan Liu,
chemodynamic therapy using Mingyuan He, Wenbo Bu*
Fenton reactions or Fenton-like
reactions to generate ·OH at tumour Page No. – Page No.
sites are discussed in depth in this
Chemodynamic Therapy: Tumour
minireview, with an emphasis on the
Microenvironment-Mediated Fenton
strategies designed to enhance

Accepted Manuscript
and Fenton-Like Reaction
therapeutic efficiency, providing
guidelines for potential clinical
translation.

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