Cancer Treatment through Nanoparticle-Facilitated Fenton Reaction

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Cancer Treatment Through Nanoparticle Facilitated Fenton Reaction Hadi Ranji-Burachaloo, Paul Andrew Gurr, Dave E. Dunstan, and Greg G. Qiao ACS Nano, Just Accepted Manuscript • DOI: 10.1021/acsnano.8b07635 • Publication Date (Web): 20 Nov 2018 Downloaded from http://pubs.acs.org on November 20, 2018

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Cancer Treatment Through Nanoparticle Facilitated Fenton Reaction Hadi Ranji-Burachaloo†‡, Paul A. Gurr†, Dave E. Dunstan‡*, Greg G. Qiao†* †Polymer Science Group and ‡Complex Fluids Group, Department of Chemical & Biomedical Engineering, The University of Melbourne, Parkville, VIC 3010, Australia. KEYWORDS: fenton, iron, nanoparticles, chemotherapy, photodynamic therapy, photothermal therapy, cancer, treatment.

ABSTRACT. Currently, cancer is the second largest cause of death worldwide and has reached critical levels. In spite of all the efforts common treatments including chemotherapy (CT), photodynamic (PDT), and photothermal therapy (PTT), suffer from various problems which limit their efficiency and performance. For this reason, different strategies are being explored which improve the efficiency of these traditional therapeutic methods or treat the tumor cells directly. One such strategy utilizing the Fenton reaction has been investigated by many groups for the possible treatment of cancer cells. This approach is based on the knowledge that high levels of hydrogen peroxide exist within cancer cells and can be used to catalyse the Fenton reaction leading to cancer killing reactive oxygen species (ROS). Analysis of the current literature has shown that due to the diverse morphologies, different sizes, various chemical properties and the tunable structure of nanoparticles, nanotechnology offers the most promising method to facilitate the Fenton reaction with cancer therapy. This review aims to highlight the use of the Fenton reaction using different nanoparticles to improve traditional cancer therapies and the emerging Fenton

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based therapy, highlighting the obstacles, challenges and promising developments in each of these areas.


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Cancer which is the second greatest cause of death worldwide has reached critical levels.1 It encompasses a large number of diseases in which abnormal cells rapidly divide and spread to other parts of the body.2 Over the past several decades, significant progress has been made towards a better understanding and control of the various forms of cancer. It has been reported that nanotechnology has made significant improvements in the fields of cancer diagnostics3, therapy.5,

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and

In this way, many different nanoparticles that are responsive to the tumor

microenvironment have been developed.7,

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These agents are stable in normal physiological

environments, and undergo physical and chemical changes when exposed to various conditions found in cancer cells9 including pH,10, 11 enzyme,12 reducing conditions13 and reactive oxygen species (ROS).14 ROS are produced from the partial reduction of molecular oxygen (O2) which is required for the normal metabolism of all aerobic organisms by the provision of energy through four electron reduction reactions.15 As shown in Figure 1, oxygen gains 4 electrons and is converted to water during this process. The first reaction is a reduction of oxygen to superoxide (O2•-) which is then converted to hydrogen peroxide (H2O2) by a further one electron reduction. Next is the reduction of H2O2 to the hydroxyl radical (OH•) which is finally converted to water (H2O) by the addition of a further electron.16


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Figure 1. Electron transport chain and oxygen reduction processes in living cells. An unavoidable consequence of partial reduction of oxygen is the production of ROS which can be categorized into two groups, free oxygen radicals (O2•- and OH•) and non-radical ROS (H2O2). 17

Under natural physiological conditions, aerobic organisms develop strategies to control the

generation of ROS. For example, in living tissue, O2•- can be converted into H2O2 by superoxidedismutase (SOD) isoforms, thus reducing their ability to cross cell membranes.18 However, hydrogen peroxide as a non-radical ROS is a stable molecule, and can easily diffuse and across biological cell membranes.19 In addition, in normal cells, it is controlled by catalase which converts it to water.20 Due to metabolic and peroxisome activity, increased cellular receptor signaling, oncogene activity and mitochondrial malfunction, cancer cells generate more ROS than normal cells.21, 22 Although low levels of ROS play important roles in supporting cellular life cycles, such as proliferation,23 high concentrations, like those found in the cancer cells have the ability to damage cellular constituents effectively.24 Among all ROS, H2O2 is generally regarded as the most abundant and stable non-radical reactive oxygen species in cancer cells.19 It can easily diffuse


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across biological membranes and can be converted to hydroxyl radicals (OH•) in the presence of iron (Fe2+ and Fe3+), according to the Fenton and Fenton-like reactions (Equation 1 and 2).25 Fe2 + + H2O2→Fe3 + + HO. + OH ―

(1)

Fe3 + + H2O2→Fe2 + + HO2. + H +

(2)

Iron is essential for many life processes, including cell growth, proliferation and oxygen delivery.26, 27 It is bound and transported in the body via transferrin and stored in cells within two major proteins: ferritin and hemosiderin.28 However, a constant balance between iron uptake, transport, storage, and utilization is required to maintain iron homeostasis.29 Due to the pro-oxidant effects, excessive amounts of iron are associated with increased toxicity in biological systems.30 It has been reported that iron overload in the body increases the risk of liver cancer, which is a major organ for iron storage.31 On the other hand, excess iron can react with overproduced H2O2 in cancer cells and can induce hydroxyl radical formation via the Fenton reaction. Besides iron, this reaction can be catalysed by other cations such as Mn2+, Cu1+, V2+ and, Cr4+ through Fenton-like reactions.25 Due to their strong reactivity with biomolecules, hydroxyl radicals are capable of doing more damage to biological systems, than any other ROS. 32 The OH• is able to attack and oxidase most organic molecules with high rate constants usually in the order of 106–109 M−1 s−1.33 For instance, in living cell environments, it does not diffuse from the generation site and instead rapidly oxidizes any surrounding biomacromolecules.34 Specific examples caused by high OH• concentrations include the oxidation of polyunsaturated fatty acids in lipids (lipid peroxidation),35 oxidation of amino acids in proteins,36 and DNA damage37 in both normal and cancer cells. Because of the dual properties of high H2O2 and hydroxyl radical concentrations in cancer cells, there has been growing interest in the development of therapeutic agents which produce high levels of OH• using the Fenton reaction in the tumor environment. Due to the small size, large surface


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area and high reactivity of nanomaterials, nanoparticles take part as catalysts in the generation of hydroxyl radicals by the heterogeneous Fenton reaction.38 Iron oxide nanoparticles, Fe3O4 and αFe2O3 can react with H2O2 and produce OH• at low pH.39 Other metal oxide nanoparticles such as manganese, palladium, silver, copper and gold are also capable of decomposing H2O2 into OH• through Fenton-like reactions.40 Recent studies have shown that nanoparticles can take part as catalysts in the generation of OH• by heterogeneous Fenton-like reactions in biological systems, which is highly dependent on the physicochemical properties of particles including, size, shape, chemical composition and surface structure.41 Because of the strong reactivity of hydroxyl radicals,42 it is being investigated for specific biomedical treatment applications, such as direct destruction of cancer cells43 or enhancing photodynamic therapy (PDT),44 upgrading photothermal therapy (PTT),45, 46 improving chemotherapy.47 In this review we have extended the scope of the recently reported mini-review which outlined the effects of tumour microenvironment on Fenton reaction,48 to include all of the reported cancer treatment strategies which involve the Fenton reaction using various nanoparticles (Figure 2).

Figure 2. The summative scheme for the Fenton reaction in cancer cell therapy.


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Fenton Based Therapy Recently, the Fenton reaction has been reported and used to treat and destroy cancer cells directly. Various groups have used Fe3O4, α-Fe2O3,49 silver,50 gold,51 MnFe2O4,52 and FeOxMSNs53 to produce OH• radicals via the classical Fenton reaction within the acidic lysosome environments. However, most of the reported nanoparticles only produced low levels of OH• via a heterogeneous reaction, and hence are unable to treat the cancer cells using the endogenous H2O2 alone. As a result, various modifications of the classical Fenton reaction, such as photo-Fenton54 and sono-Fenton55 have been reported to improve the oxidation efficiency in the cancer cell biological system. The following discussion will be divided into two sections, namely classical Fenton based therapy and modified Fenton based therapy. Finally, the obstacles and challenges of each section are suggested and discussed in a separated section. Classical Fenton Based Therapy A number of research groups have investigated the efficacy of various iron based nanoparticles in treating cancer cells which contain sufficient amounts of H2O2 to enable the Fenton reaction to produce ROS in-situ. For example, Zhang et al., reported synthetic magnetic nanoparticles (MNPs) as a Fenton reagent (FR) for anti-bacterial, in vitro and in vivo tumor treatment.56 However cell viability studies showed that their MNPs (20 µg/mL) were unable to treat cancer cells using endogenous H2O2 alone, and more than 85% of HeLa cells were still alive after treatment. Extensive apoptosis of the cancer cells was only observed upon the addition of 400 µM exogenous hydrogen peroxide. In addition, an approximately 99% tumor inhibition ratio was shown by the combination of intravenous injection of MNPs and intratumoral injection of H2O2 after treatment for 17 days.56


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In another effort, Fu and co-workers presented a facile in situ redox method which used mesoporous silica nanomaterials with iron oxides (FeOx-MSNs) introduced into the pores to catalyze the decomposition of H2O2, producing considerable ROS selectively inside the acidic lysosomes of cancer cells.57 It is reported that exogenous hydrogen peroxide promoted the nanoparticles toxicity so that the cell viability of cancer cells incubated with 100 µg/mL FeOxMSNs and 100 µM H2O2 significantly decreased from 96.2% to 40.6%. In 2016, an amorphous iron nanoparticle was used by Zhang et al. to generate OH• inside the cancer cells using endogenous H2O2.58 This nanoparticle was ionized in acidic tumors and released iron, which in turn induced localized Fenton reactions. The rate of OH• generation using free Fe2+ ions was found to be faster than Fe2+ on the surface of Fe3O4 nanoparticles.59, 60 Due to the low level of H2O2 produced by MCF-7 cancer cells, synthesised amorphous iron nanoparticles were not able to treat the cancer cells in in vitro study, so in this case exogenous H2O2 was added. However, a complete inhibition of tumor growth was reported after 16 days intratumoral nanoparticle injection for an in vivo study. In contrast, intravenous injection displayed much lower anticancer efficacy than the intratumoral injection group even under magnetic targeting.58 In a similar study Wang et al. reported the iron engineered framework of mesoporous silica nanoparticles (rFeOx-HMSN) as a Fenton reagent (FR) for in vitro and in vivo tumor treatment.61 Under protein-rich tissue environments, the nanoparticles readily collapsed releasing Fe2+ and Fe3+ and destroying the cancer cells through the Fenton reaction. The cell viability of cancer cells decreased to less than 30% at 50 µg/mL rFeOx-HMSN and 50 µM exogenous H2O2 at pH=6.0. For an in vivo study, the inhibition of tumor growth was reported after 15days for both intratumoral and intravenous nanoparticle injection.61


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In an interesting study reported by Xu and co-workers in 2009, it was demonstrated that FePt nanoparticles can function as another type of agent for controlled cancer therapy using endogenous H2O2.62 The FePt was also released Fe ions due to the low pH in tumor cells, which catalyzed H2O2 decomposition into OH• within the cells and further induce cancer cell apoptosis. Incubation of different cells with the Fe40Pt60 nanoparticles produced a dose-dependent reduction in cell viability at Fe concentrations of 0-8.6 μg/mL. For A2780 cells, the Fe40Pt60 nanoparticles have an IC50 of 1.25 μg Fe/mL.62 In 2016, Yue et al. used graphene oxide to improve the delivery of FePt nanoparticles inside the cancer cells.63 FePt nanoparticles were assembled on graphene oxide (GO) surfaces to form FePt/GO nanocomposites then conjugated with folic acid. Synthesised nanocomposites could effectively target and show significant toxicity to FA receptor-positive tumor cells, but with no obvious toxicity to FA receptor-negative normal cells.63 The cytotoxicity of the FePt-based nanocomposite showed significant toxicity toward MCF-7, HeLa, and HepG2 cells, with corresponding IC50 values of 40, 52, and 47 μg/mL, respectively.63 The same research group then reported the synthesis of FePt-Au-meso-2,3-dimercaptosuccinic acid/PEG-FA nanoparticles which presented high bio-stability in physiological solutions and successfully targeted folate acid receptor-positive cancer cells.64 The tumor growth of mice with an intratumor injection of nanoparticles was more severely inhibited than the control and those treated with an intravenous injection, which attributed to the relatively low transport efficiency through the vessels and organs. However, attempts at using FePt nanoparticles raise issues of biocompatibility, stability, and low selectivity because of potential metal (Pt) contamination.63, 65 Lee et. al reported that SnFe2O4 nanocrystals are able to internalize and treat the cancer cells using endogenous H2O2 through the heterogeneous Fenton reaction.66 As the reported nanoparticle only produced OH• at the surface via a heterogeneous reaction, needed a high concentration to be


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toxic to the cancer cells. Reported IC50 values for SnFe2O4 nanocrystals is 148 μg/mL, which is significantly higher than similar studies.66 A reduced metal organic framework (rMOF) nanoparticle with a mesoporous structure was synthesised and presented by Ranji-Burachaloo and co-workers in 2017.43 rMOF conjugated with folic acid took advantage of the overexpression of folate receptors and transport into the tumor cells by receptor mediated endocytosis. The rMOFFA then internalized and migrated to intracellular compartments called endosomes, which has a pH range from 4.3 to 6.9 (most frequently pH 5.0).67 The nanoparticles then rapidly induced the generation of a large amount of OH• through the heterogeneous and homogeneous catalysis of the Fenton reaction (Figure 3A). Reported results showed a concentration-dependent phenomenon for HeLa cells, which cell viability decreasing dramatically at low concentration (Figure 3B). This nanoparticle was significantly more toxic to HeLa than noncancerous fibroblasts (NIH-3T3) cells with IC50 values of 43 and 105 μg/mL, respectively (Figure 3C).43

Figure 3. (A) Schematic mechanism of cancer cells treatment using rMOF-FA nanoparticles B) Cytotoxicity of rMOF-FA toward HeLa and NIH-3T3 cells (C) Comparison of the IC50 values of the rMOF-FA in NIH-3T3 cells vs HeLa cells ref. 43. Copyright 2017. Reproduced with permission from the American Chemical Society Group


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In a follow-up study by the same research group, the size of rMOF nanoparticle decreased due to surface PEGylation via surface-initiated atom transfer radical polymerization to produce [email protected] As a result of the hydrophilic polyethylene glycol (PEG) chains, the P@rMOFs were completely dispersed and stable in aqueous solution. In-vitro cell cytotoxicity experiments demonstrated that the HeLa cell viability decreased dramatically to 22% while the NIH-3T3 cell viability remained more than 90% after 24 h incubation for 2P@rMOF-FA (2:1 mass ratio). Importantly, the selectivity index was 4.48 which is the highest value reported for cancer apoptosis using classical Fenton based therapy.68 Antioxidant defences in the cancer cells are the most challenging obstacles for Fenton based therapy. Some antioxidant enzymes such as catalase and glutathione (GSH) peroxide have H2O2 and OH• scavenging abilities which greatly reduce the therapeutic efficiencies.34, 69 Therefore, GSH depletion has been recognised as a good strategy to increase Fenton treatment efficiency. Following this idea, Lin et. al reported that MnO2-coated mesoporous silica nanoparticles (MSN@MnO2) undergoes a redox reaction with GSH to form glutathione disulfide and Mn2+. Subseqeuenlty, the produced Mn2+ exerts Fenton-like activity to generate OH• from endogenous H2O2, killing the cancer cells (Figure 4).70 Based on in vitro results, PEGylated MSN@MnO2 nanoparticles exhibited significantly greater anticancer efficacy relative to MnCl2, which could be attributed to both the excellent Fenton-like Mn2+ delivery and GSH depletion capabilities of the MnO2 shell (Figure 4B). In addition, according to in vivo results, tumor growth was greatly inhibited after 14 days of intravenous injection of MSN@MnO2 nanoparticles nanoparticle at dosage of 4.0 mg/kg (Figure 4C).70


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Figure 4. (A) The mechanism of MnO2 as a smart chemotherapeutic agent for enhanced Fenton based therapy. (B) Cytotoxicity of MnCl2, MS@MnO2 MS@MnO-CPT (control drug: camptothecin) nanoparticles toward U87MG cells. (C) Tumor volume change after injection of different nanoparticles after 14 days ref. 70. Copyright 2017. Reproduced with permission from the John Wiley& Sons Inc Group. Modified Fenton Based Therapy To improve the oxidation efficiency in cancerous biological systems, various modifications of the classical Fenton reaction have been investigated utilizing either photo-Fenton or sono-Fenton reactions. Photo-Fenton utilizes a combination of hydrogen peroxide and UV radiation in the presence of iron Fe2+ and Fe3+ to produce more hydroxyl radicals than conventional Fenton methodology.71, 72 The classical Fenton reaction does not proceed once all Fe2+ ions are consumed. However, the regeneration of Fe2+ by photo-reduction of Fe3+ occurs in photo-Fenton reaction.73 The generated Fe2+ reacts with H2O2 and generates hydroxyl radical and the process continues.54 In a study published by Hauser et al., radiation has been used to increase the efficiency of Fe3O4


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nanoparticles conjugated with TAT peptide in tumor microenvironments.74 The cell viability of A549 lung carcinoma treated by combined treatment of Fe3O4-TAT nanoparticles and 5 Gy radiation therapy, decreased to 48% after three days which was significantly lower than the expected outcome of solely Fe3O4-TAT nanoparticles (90.4%) or radiation (72.6%), indicating the treatments synergistic effects.74 In a study by Hu et al. in 2017, another strategy of photo-Fentonchemotherapy was reported.75 The designed agent consists of three key components: (i) upconversion nanoparticle cores based on lanthanide-doped nanocrystals for converting NIR light to UV or visible photons to catalyze the photo-Fenton reaction; (ii) Mesoporous silica shells coated on the upconversion nanoparticles core for FR (Fe2+) loading and delivery; and (iii) Ru2+ complex co-conjugated on the surface of mesoporous silica shell to bind mitochondrial DNA (namely, UCSRF). Under NIR irradiation, the generated H2O2 in cancer mitochondrion can react with Fe2+ to produce localized OH• radicals, which cause mtDNA damage (Figure 5A).75 In vivo results showed that the UCSRF samples could almost completely prevent tumor growth after 12 days irritated 1.0 W/cm2 without any abnormal behavior or significant mice weight loss (Figure 5B).75


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Figure 5. (A) Improved Fenton treatment efficiency using photo-chemotherapy (B) Tumor volume change after injection of UCSRF nanoparticles after 12 days ref. 75. Copyright 2017. Reproduced with permission from the Elsevier Ltd In a similar study Bi et al. reported upconversion nanoparticles (UCNPs)-platinum(IV)-ZnFe2O4 as

photo-Fenton-chemotherapy reagents for cancer treatment.76 The UCNPs-platinum(IV)-

ZnFe2O4 break apart when they enter the cells owing to the reducing property of glutathione. Under NIR irradiation, ZnFe2O4 reacts with endogenous H2O2 and generates localized OH• radicals, which damage cancer cells. At the same time, platinum molecules bond to DNA and inhibit the DNA replication. A complete inhibition of tumor growth was reported after 14 days intravenous nanoparticle injection.76 In a follow-up study, the same research group, reported the synthesis of UCNPs encapsulated iron MOFs nanoparticles (UCNPs@MIL-100(Fe)).77 The in vivo experimental studies demonstrated that the administration of UCNPs@MIL-100(Fe) significantly inhibited the growth of tumors due to the production of high concentrations of OH• following the Photo-Fenton therapy.77


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In an interesting study reported by Li et al., sonication has been used to increase the concentration of hydroxyl radicals in tumor environments.55 For this study, poly(lactic acid-coglycolic acid) (PLGA) polymersome comprising of H2O2 encapsulated in the hydrophilic core, and Fe3O4 nanoparticles packed into the shell (H2O2/Fe3O4−PLGA) was synthesized. Upon exposure of the nanoparticles to the micro ultrasound diagnostic system, the encapsulated hydrogen peroxide in the core was liberated and moved by means of disrupting the PLGA polymersome, to react with iron oxide packed inside the shell of the polymersome membrane, thus producing a high concentration of OH• following the Fenton reaction. This process showed a prominent cancer cell killing effect (Figure 6A). After 22 days of intravenous injection of H2O2 (600 μL)/Fe3O4−PLGA (5 mg [Fe]/kg) in the presence of ultrasound, tumors were effectively eliminated, without any apparent changes in mice weight (Figure 6B).55

Figure 6. A) Cancer cell treatment using H2O2/Fe3O4−PLGA nanoparticles B) Tumor volume change after injection of different nanoparticles after 22 days ref. 55. Copyright 2016. Reproduced with permission from the American Chemical Society Group.


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Limitations of Fenton Based Therapy The challenges of classical Fenton based therapy as a newfound methodology still remain. As most of the reported nanoparticles only produced OH• at their surface via a heterogeneous reaction, high concentrations of reagents were needed to be toxic to cancer cells. Despite the limited attempts to use nanoparticles which released Fe2+ inside the cancer cells, these were largely restricted due to their low stability, high aggregation, and poor selectivity. Although, photo-Fenton and sono-Fenton systems upgrade the nanoparticles efficiency at low concentrations, they still suffer from various problems which will be mentioned in the following section. Low penetration depth and limited localised irradiation and sonication still limit the use of these approaches using the currently available technologies. Due to the current limitations of both classical and modified Fenton based therapy, future studies for developing of other agents are needed to be applicable in real situations. Enhancing Traditional Therapies using the Fenton Reaction Current cancer treatment options include a combination of photodynamic, photothermal and chemotherapy.78 Despite the extensive efforts in refining these techniques, these strategies still suffer from various complications, decreasing their efficiency and performance.79 Therefore, interesting different strategies have been utilized to enhance effectiveness of these common therapeutic approaches. Due to the strong reactivity of hydroxyl radicals,42 which are produced by the Fenton reaction, many studies have aimed at harnessing this reactivity in approaches for cancer therapy. As will be discussed, this approach can diminish some of the disadvantages of traditional therapies, and in some case through a synergistic effect, increase the therapeutic performance.


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Fenton Enhanced Photodynamic Therapy PDT has emerged as a promising therapeutic strategy for various types of cancers.80 In this method, light is used to activate the various photosensitisers, which can react with molecular oxygen and generate the reactive oxygen species (ROS)(Figure 7A).81 However, therapeutic effects of this method are restricted due to problems of hypoxia and the low oxidation performance of the ROS.82 Recently, different nanoparticles have been designed to overcome these issues by enhancing the therapeutic efficiency using the Fenton reaction. A sufficient amount of O2 for PDT can be continuously produced via the Fenton reaction in an H2O2-rich cancer microenvironment.44, 83

In this regard, nanoparticles can work as a Fenton catalyst and convert the intracellular H2O2 to

molecular oxygen through Haber–Weiss reactions (Equation 1, 3 and 4).84,

85

Then, delivered

photosensitiser (PS) molecules are able to react with generated O2 and produce high concentration of reactive oxygen species (Figure 7B).44, 83 Fe2 + + H2O2→Fe3 + + HO. + OH ―

(1)

HO. + H2O2→H2O + O2. ― + H +

(3)

O2. ― + H + + H2O2→O2 + HO. + H2O

(4)


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Figure 7. (A) Schematic illustration of a typical photodynamic reaction. (B) Delivery of Fenton agent and photosensitiser into the cell and subsequent Fenton reaction within the H2O2-rich cancer microenvironment. Manganese dioxide nanoparticle has been recently developed by different groups to increase the level of oxygen in cancer tissues.44, 86, 87, 88 In a study reported by Kim et al. in 2017, it was shown that manganese ferrite nanoparticle anchored mesoporous silica nanoparticles (MFMSNs) can react with H2O2 through the Fenton reaction and increase intracellular O2 levels to effectively enhance the efficacy of photosensitizer chlorin e6 (Ce6).44 The amount of singlet oxygen species (O2·) generated inside the cancer cells using MFMSNs loaded with Ce6, was 2.2 times more than cells incubated with free Ce6. As an in vivo result, it has been reported that the tumor size of the laser-irradiated MFMSN-Ce6 group was dramatically reduced compared with that of the laserirradiated Ce6, indicating that sufficient amounts of oxygen generated by MFMSNs, inside tumors, resulted in the enhancement of the therapeutic effects.44 In another study reported by Lan et al., a nanoscale metal-organic framework containing iron and tetra(p-benzoato)porphyrin (TBP) ligand were prepared, and utilized for enhancing PDT efficiency.83 This interesting nanoparticle convert intracellular hydrogen peroxide into oxygen


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using iron through the Fenton reaction. The produced O2 then significantly improved the efficacy of anti-programmed death-ligand 1 (α-PD-L1) treatment.83 PDT has also been shown to be limited due to the low oxidation performance of ROS such as singlet oxygen.82 However, the Fenton reaction can produce an abundance of ROS such as hydroxyl radicals, with notably stronger oxidation capability than singlet oxygen.89 To this end, several groups have reported using the Fenton reaction to improve PDT by increasing the concentration of the generated ROS.75, 90, 91 Ju et al. reported combining graphitic carbon nitride and copper, to generate Cu+–g-C3N4, which demonstrated synergistic therapeutic properties in the presence of light.90 It is reported that Cu+–g-C3N4 catalyzed the reduction of molecular oxygen to singlet oxygen, and hydrogen peroxide to hydroxyl radical, both of which facilitated the PDT. Final quantitative analysis in this study showed that the irradiation of Cu+–g-C3N4 with light, led to more dead cells than that of g-C3N4, which was consistent with the amount of intracellularly generated ROS. In a similar study Cioloboc et al. reported conjugating zinc(II)-protoporphyrin (ZnP) with the iron storage protein bacterioferritin (Bfr) which targeted delivery of both the photosensitizer and iron (Figure 8).92 It was reported that the ZnP triplet excited state, 3ZnP*, produced singlet oxygen in cancer environments. In addition, it reduced Fe3+ in the enclosed [FeO(OH)]n core to the Fe2+, which then diffused out of the protein shell and underwent the Fenton reaction in the presence of H2O2. Reported IC50 values for this strategy were 220 and 160 nM for the empty and iron-loaded nanoparticles, respectively.92


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Figure 8. Schematic illustration for photosensitized targeting of singlet oxygen and Fenton reactive iron to cancer cells using the Bfr delivery platform.92 Copyright 2017. Reproduced with permission from the American Chemical Society Group. Fenton Enhanced Photothermal Therapy PTT has been used for the treatment of cancer cells, whereby the cells are heated by electromagnetic radiation (most often in infrared wavelengths), which causes the cell membranes to loosen and the proteins to denature leading to cell destructuion.45 However, it is sometimes necessary to increase the surrounding temperature of the tumor cells to more than 60 oC, to completely destroy the cancer cells. This in turn leads to the collateral damage of healthy cells, decreasing the therapies effectiveness. Using a combination of Fenton and PTT, Tang and coworkers observed a synergetic effect with improved therapeutic performance and reduced normal cell damage due to non-targeted heating of the surrounding environment.93 It has been shown that the heat generated from the photothermal conversion can accelerate and increase the quantity of hydroxyl radicals formed. For this aim, antiferromagnetic pyrite nanocubes (FeS2) as a FR and photothermal reagent (PR) were prepared, conjugated with PEG and utilized for in vitro and in vivo studies (Figure 9A). In the presence of both FeS2–PEG (100 ppm Fe) and exogenous H2O2


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(100 µM), the inhibition in 4T1 cell viability amounted to more than 25%. Interestingly, the viability of cancer cells decreased to less than 20% under laser irradiation at 1.5 W/cm2 (Figure 9B). In vivo studies reported a notable reduction in tumor volume after 18 days of an intravenous injection of FeS2–PEG (50 mg Fe/Kg) and irradiation at 1.5 W/cm2 laser (Figure 9C).93

Figure 9. (A) Schematics illustration of the FeS2-PEG mediated PTT. B) 4T1 cells viability at different pH and various concentration of FeS2-PEG C) Tumor volume change after injection of FeS2-PEG after 18 days ref.

93.

Copyright 2017. Reproduced with permission from the John

Wiley& Sons Inc Group. Recently Liu et al. reported copper ferrite nanospheres (CFNs) as “all in one” treatment agents which can enhance both photothermal and photodynamic methods. As shown in Figure 10A, CFNs nanoparticles can catalyse H2O2 and produce O2 through the Fenton reaction enhancing photothermal therapy. In addition, this nanoparticle showed an enhanced photothermal performance under laser irradiation (λ = 808 nm), thus improving photothermal therapy. Importantly, the Cu2+ and Fe3+ in the nanoparticles can also react with hydrogen peroxide via the Fenton reaction and produce high concentrations of hydroxyl radicals.94 Based on the in vivo


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results, CFNs were shown to completely stop tumor growth after 15 days (Figure 10B) while no significant changes in the mice body weight was observed (Figure 10C).94

Figure 10. (A) Schematic illustration of the CFNs mediated PTT and PDT. (B) Tumor volume change after injection of CFNs after 15 days (C) Changes in the body weight of tumor bearing mice during treatment.94 Copyright 2018. Reproduced with permission from the American Chemical Society Group. Fenton Enhanced Chemotherapy Chemotherapy (CT) is a familiar method of cancer treatment which utilizes anti-cancer drugs to destroy and eliminate cancer cells. Drug resistance and chemical toxicity are the major clinical chemotherapeutic drawbacks of this method.95 However, it has been proposed that co-delivery of therapeutics has synergistic effects and is capable of eliminating the problem of drug resistance in tumors.96 Recently, the combination of chemotherapeutic drugs and Fenton agents have been reported to enhance the anticancer activity and improve treatment efficiency.51, 97, 98, 99, 100 Various drugs such as β-lapachone,101,

102

cinnamaldehyde,103,

104

doxorubicin,100,

105, 106, 107, 108

and

cisplatin98 were shown to undergo redox cycles to generate and increase high H2O2 levels inside living cells. Another approach reported the use of NO, CN, SiO2 and H2S chemicals to capture and


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inhibit catalase enzyme and thus increasing the concentration of H2O2 produced in living cells. 109, 110, 111, 112, 113

In each of these cases, the increased hydrogen peroxide concentrations were

converted to hydroxyl radicals using Fenton agents to selectively treat the cancer cells (Figure 11).

Figure 11. Schematic illustration of improving anticancer activity and treatment efficiency by a combination of chemotherapeutic drugs for increasing H2O2 levels and Fenton agents for enhancing hydroxyl radicals. The strategy developed by Huang et al. reported pH-responsive superparamagnetic iron oxide nanoparticle micelles working synergistically with β-lapachone to improve cancer therapy.114 βLapachone underwent a redox cycle to generate elevated superoxide (O2•-)101,

102

which was

converted into H2O2 by superoxide dismutase isoforms,115 causing massive hydrogen peroxide levels. These micelles selectively released iron ions inside cancer cells, which then interacted with the hydrogen peroxide within the tumor. They reported that a 10-fold increase in ROS stress was detected in β-lapachone exposed cells, pre-treated with Fe3O4-micelles over those treated with βlapachone alone, which was also confirmed with significantly increased cell death.114 In another


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study, An et al. reported the use of ascorbic acid, a known antioxidant,116 to produce endogenous H2O2 and accelerate tumor treatment using the Fenton reaction.117 In this study, Fe3O4@carbon nanoparticles were synthesized and then modified with folic acid to increase the particles’ initialization using the over-expression of folate receptors on the surface of cancer cells.118 The carbon shell of iron nanoparticles contains partially graphitized carbon and facilitates electron transfer in the catalytic decomposition of H2O2, leading to the production of highly reactive hydroxyl radicals. Cancer cell apoptosis reached 61% in the presence of 20 µg/mL Fe3O4@carbone folic acid nanoparticles and 2 mM ascorbic acid, as opposed to a solution of ascorbic acid alone which reached 25%.

117

According to the literature, ascorbic acid can be oxidized to ascorbate

radical in the presence of metalloprotein catalyst, donating an electron to oxygen to produce superoxide radical (O2•-) which is finally converted to H2O2 in the cancer cells.119 A similar strategy was developed by Maji et al. in 2015, in which another nanoparticle (GSF@AuNPs) was prepared by the immobilization of gold nanoparticles on mesoporous silica-coated nanosized reduced graphene oxide conjugated with folic acid. GSF@AuNPs had the ability to react with high concentrations of hydrogen peroxide, produced by ascorbic acid inside the HeLa cells and increase the cancer cell apoptosis to 61% after 48h incubation.51 Recently, another similar strategy has been reported by Wang et al., where polymeric micelles were prepared via the self-assembly of poly(ethylene glycol)-block-Poly(γ-propargyl-L-glutamat-graf t-β-cyclodextrin), L-ascorbyl palmitate, and ferrocenecarboxylic acid hexadecyl ester in aqueous solution. L-ascorbyl palmitate molecules act as the prooxidant agents to generate H2O2 in tumor tissues which then transformed into highly toxic hydroxyl radical under the catalysis of ferrocene via the well-known Fenton reaction.120 Here the IC50 values of L-ascorbyl palmitate/ferrocene-micelles against 4T1 and MCF-


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7 cells were both 73 μg/mL, with L-ascorbyl palmitate-equivalent concentrations of 24 μg/mL, much lower than that of free L-ascorbyl palmitate.120 The natural flavonoid cinnamaldehyde (CA) has been shown to generate and increase the hydrogen peroxide inside cancer cells.103, 104 In this regard, Kwon et al. developed Nano-Fenton reactors as a anticancer therapeutic agent, which releases cinnamaldehyde (CA) under acidic environments, to generate H2O2 that is rapidly converted into hydroxyl radicals by ferrocene, leading to apoptotic cancer cell death.97 Based on the in vivo results, reduction in tumor volume was observed with these Nano-Fenton reactors, which generated toxic hydroxyl radicals via the Fenton reaction, without apparent changes in mice body weight.97 The well-known chemotherapy drug Doxorubicin (Dox) has been utilized by Kankala et al. to increase the intracellular hydrogen peroxide, which is then converted to cytotoxic free radicals through a copper(II)-catalyzed Fenton-like reaction. In this example, copper(II)–doxorubicin complexes were prepared which were conjugated on the surface of double-layered hydroxide nanoparticles.100 The results uncovered that the Dox released through the dissociation of the pHsensitive link in nanoconjugates and effectively inhibited the growth of MES-SA/Dx-5 cells (IC50 0.9 µg-DSox/mL). In a follow-up study by the same research group, Dox was conjugated to copper metal in the copper-substituted mesoporous silica nanoparticles framework (Cu-MSN-Dox) through a pH-sensitive coordination link, which is acutely sensitive to the tumor’s acidic environment.105 The reported half-maximum inhibitory concentration value (IC50) decreased to 0.35 µg-Dox/mL for Cu-MSN-Dox nanoparticles. Coating of Cu-MSN-Dox nanoparticles with liposome improved the toxicity and decreased the IC50 value to 0.18 µg-Dox/mL.105 In an interesting in vivo study developed by Ma and co-workers, iron oxide nanocarrier was used to deliver the commercial prodrug cisplatin(IV)121 inside the tumor cells.98 The loaded prodrug


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rapidly reduced to toxic cisplatin which subsequently formed Pt-DNA adducts and activated nicotinamide adenine dinucleotide phosphate oxidase (NADPH), triggering a cascade reaction to form H2O2. At the same time, iron oxide nanocarrier degraded inside the cells and was metabolized in the cancer cells, releasing excess labile iron ions that catalyzed H2O2 decomposition into highly toxic hydroxyl radical (Figure 12A). Using this nanocarrier the tumor growth after 14 days, was greatly inhibited to a 5-fold increase in relative tumor volume compared to a 50-fold increase when unloaded iron carrier was used (Figure 12B).98

Figure 12. (A) Schematic illustration for improving anticancer activity and treatment efficiency by a combination of cisplatin(IV) and iron oxide (B) Tumor volume change after injection of FePt nanoparticles after 14 days ref.

98.

Copyright 2017. Reproduced with permission from the

American Chemical Society Group Recently, a similar strategy has been published by Huo et al. that incorporated natural glucose oxidase (GOx) and ultra-small Fe3O4 nanoparticle thus fabricating a sequential nano-catalyst for selective tumor modalities.122 GOx was used as the enzyme to catalyze the oxidation of glucose to abundant amounts of hydrogen peroxide in the tumor region. Iron oxide nanoparticles were then


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able to decompose H2O2 into highly toxic hydroxyl radicals through the Fenton reaction under the tumor’s acidic conditions, which then caused cancer cell death (Figure 13A). The in vivo therapeutic performance of the synthesised nanoparticles exhibited a highly desirable tumorsuppressive effect toward the 4T1 mammary tumor xenograft, both intravenously (64.7%, Figure 13B) and intratumorally (68.9%, Figure 13C) at a dosage of 10 mg/kg.122 The similar strategy has been reported by Tan et al. that hydrogel particles was utilized to transfer the GOx and Fe3O4 nanoparticle into cancer cells and treat them.123

Figure 13. (A) Schematic illustration of glucose oxidase and Fe3O4 nanoparticles integrated into the biodegradable dendritic silica nanoparticles for producing high levels of OH•. Tumor volume change after injection of (B) intravenous (C) intratumoral injection of nanoparticles after 15 days ref. 122. Copyright 2017. Reproduced with permission from the Nature Group. Catalase is a common enzyme found in nearly all living organisms exposed oxygen and catalyzes the decomposition of hydrogen peroxide to water and oxygen.124 Catalase-imprinted can be


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another strategy to increase H2O2 concentration in the tumor cells. Following this idea, catalaseimprinted Fe3O4/Fe@fibrous SiO2/polydopamine nanoparticles were reported by Chen et al. to increase endogenous hydrogen peroxide within cancer cells and treat them via the Fenton reaction.125 In this study, the catalase-imprinted layer selectively captures the catalase in cells inhibiting its activity and thus leading to a high H2O2 concentration. Simultaneously, the Fe3O4/Fe nanorod core releases iron ions to convert the homolysis of H2O2 into OH• radicals. Toxicity results showed that the viability of MCF-7 cells dramatically decreased from 90 to 26% as the nanoparticle concentration increasing from 10 to 100 μg/mL.125 Recently, Liu et al. developed an amorphous iron oxide-RNAi platform coated with lipid-PEG for co-targeting metabolic and hydroxyl radical homeostasis in tumor cells.126 In this method, RNAi is able to silence MCT4 to induce tumor cell acidosis and H2O2 production. Iron ions released from amorphous iron oxide then react with H2O2 to generate highly reactive and toxic OH• via the Fenton reaction. According to in vivo results, suppression of tumor growth was observed for the amorphous iron oxide-RNAi treated group, without causing a noticeable influence on the subjects body weight.126 In addition to synergetic effects, the Fenton reaction can be used for improving drug delivery of cancer agents. In a study reported by Chung et al. in 2015, ultrasensitive ROS-responsive hollow microsphere carries containing a combination of anti-inflammatory drug Dexamethasone sodium phosphate (DEX-P), an acid precursor consisting of ethanol and FeCl2, and sodium bicarbonate as a bubble generating agent were prepared. As H2O2 diffused through the hollow microsphere carriers it reacts with Fe2+ and produces OH•, which immediately reacts with ethanol to produce acetic acid. The acid then reacts with sodium bicarbonate to generate CO2 bubbles, disrupting the nanoparticle shell and releasing a high dosage of drug to the inflamed region (Figure 14).127 It was


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reported that the percentage of drug released from the nanoparticles was 85% in the inflammatory environment, which is significantly higher than 18 % in normal cells.

Figure 14. Schematic illustration of the mechanism of the H2O2-responsive gas-generating hollow microspheres and their mechanism for drug release ref.

127

Copyright 2015. Reproduced with

permission from the American Chemical Society Group Another example where the Fenton reaction was utilized for selective drug delivery was published by Wang and co-workers.47 In this study, a butyrate-inserted Ni–Ti layered double hydroxide film (LDH/Butyrate) was prepared on the surface of nitinol alloy, which can selectively inhibit tumor growth and metastasis by taking advantage of the overproduced H2O2 in the tumor environment. In this case, hydrogen peroxide was consumed by LDH/Butyrate through a Fentonlike reaction, and cytotoxic butyrate was released and delivered selectively inside the cancer cells (Figure 15A).47 Based on the in vitro cytotoxicity results, cancer RBE cells cultured on LDH/Butyrate had higher toxicity than those cultured on NiTi, and LDH alone. In addition, the cell viability of normal HIBEpiC cells cultured on all of the samples remained at a high level


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(Figure 15B). In vivo results showed that the LDH/Butyrate samples could almost completely prevent tumor growth while the body weight of the mice in bare NiTi did not have any noticeable changes (Figure 15C).47

Figure 15. (A) Schematic illustration of the mechanism of the H2O2-responsive butyrate release inside cancer cells (B) Cytotoxicity of different samples to RBE (Cancer) and HIBEpiC (Normal) cells (C) Tumor volume and mice body weight changes after 3 week treatment ref. 47. Copyright 2017. Reproduced with permission from the Elsevier Ltd. Furthermore, the Fenton reaction can activate a hydrophobic manganese carbonyl ((Mn2(CO)10) drug and treat the cancer cells using the gas therapy method. In an interesting study reported by


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Jin and co-workers, hollow MSN were utilized for Mn2(CO)10

drug

delivery (namely,

MnCO@hMSN).128 It has been reported that manganese can follow the Fenton-like reaction and convert the exogenous H2O2 to OH• radicals, which then in turn, coordinate with the Mn centre, causing the release of carbon monoxide (CO) from the Mn centre (Error! Reference source not found.A). This gas therapy method utilises the CO produced to treat tumor cells directly. This nanoparticle inhibited the growth of tumors within 22 days (Error! Reference source not found.B), while all remained alive and maintained their body weight after treatment (Error! Reference source not found.C).128 In a follow-up study by the same research group, manganese carbonyl (MnCO) based drugs adsorbed and coordinated with Ti-based metal organic framework (Ti-MOF) followed the same gas treatment strategy.129

Figure 16A) Schematic mechanism of cancer cells treatment using MnCO@hMSN following gas therapy. B) Tumor volume change after injection of MnCO@hMSN after 22 days C) Changes in


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the body weight of tumor bearing mice during treatment.128 Copyright 2017. Reproduced with permission from the Royal Society of Chemistry. Limitations of Fenton Enhanced Photothermal, Photodynamic- and Chemo- therapies Despite all the advantages of these reported studies, some essential challenges still exist for them to be taken up for cancer treatment. The major disadvantage is the co-delivery of therapeutic agents (e.g. PS or drug) and Fenton agents to the tumor microenvironment. This co-delivery can be done using separate carriers or a single carrier.130,

131

Using the separate carrier method, it is very

difficult to deliver both the therapeutic and Fenton agents to the same target at the same time, while maintaining an acceptable ratio for combinatory effects. However, the alternative of delivering both agents within a single carrier is also a challenge due to the differences in their physicochemical properties, such as hydrophobicity, molecular weight and metabolic stability.130 In addition, due to the toxicity of both delivered therapeutic and Fenton reagents to normal cells, satisfactory selectivity toward tumor tissue has been hard to achieve. To address this issue, complex delivery systems are required. Finally, photothermal and photodynamic therapies are still restricted by problems which are unresolved using the Fenton reaction. Both methods cannot be used for the treatment of advanced metastasized cancers where whole body irradiation would be required. The treatments are also hampered by limitations in the penetration depth, as an example, red light typically has a penetration depth of only 1-3 mm.82 Conclusion and Future Outlook In the last few years, the number of publications describing innovative strategies to treat cancer cells using Fenton based reactions has dramatically increased and the different methodologies outlined in this review are summarized in Table 1. Photodynamic, photothermal and chemotherapy


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as promising therapeutic strategies are limited by various problems, which decrease their efficiency and performance. Therapies which utilize the Fenton reaction, by taking advantage of the high levels of hydrogen peroxide present in cancer cells, has been demonstrated by various groups to overcome these issues and improve the therapeutic efficiency. However, co-delivery of PS/drug and Fenton agents to the tumor microenvironment is the major restriction facing Fentonphotodynamic or Fenton-chemotherapy. Studies which attempted to use classical Fenton reaction alone to destroy the tumor cells, requires high concentrations of nanoparticles in order to be toxic to cancer cells. As a result, to improve the nanoparticles efficiency, various modifications of the classical Fenton reaction have been investigated and classified as photo-Fenton and sono-Fenton reactions. This analysis of the current literature has shown that the approaches taken by various groups utilizing various Fenton based cancer therapies are producing increasingly successful results. However, due to the current limitations, the most promising direction for such future research should focus on the following important concepts: (i) Efficiency: The exogenous H2O2 produced in the cancer cells is enough to destroy tumors, if converted to hydroxyl radicals. To this aim, more effort should be focused on the classical Fenton reaction methodology to refine this exciting technique. Future studies for synthesising and development of effective Fe2+ nanoparticles and complexes are needed. (ii) Stability: Most of the reported nanoparticles in this area suffer from low stability and high aggregation. Increasing the stability for long time circulation in real microenvironments is essential for further development of this field. Modification of nanoparticles using functional polymers such as polyethylene glycol or utilizing stable organic carriers such as liposomes, dendrimers and micelles can help in this regard.


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(iii) Delivery: Like drugs, targeted delivery of the Fenton reagents is essential in controlling their damaging effects on normal tissues. To this aim, both passive and active targeting should be considered. Passive targeting can be achieved by modulating the size, shape, and surface characteristics of the Fenton nanoparticles. Nanoscale carrier systems can also be utilized for delivery of the Fenton reagents to improve the passive targeting. These carriers can be stable in normal physiological environments, but release Fenton reagents when exposed to various conditions found specifically in cancer cells. Furthermore, active targeting can be gained by taking advantage of the over-expression of receptors such as folate and transferrin on the tumor cell surface. (iv) Selectivity: Hydroxyl radicals are very reactive species which are unfortunately able to affect and destroy normal tissues. Further studies are required to optimise hydroxyl radical concentrations during treatment, which completely treat the cancer cells without adverse effects on healthy tissue. This concentration can be controlled by physical features (such as size, shape chemical composition and surface structure), nanoparticle activity and nanoparticle concentration. (v) Clinical trials: Unfortunately, in spite of all the efforts, to date, no evidence of clinical trials have been reported for any tumour therapy based on in situ catalytic chemical reactions including Fenton cancer treatment.132 We strongly believe that efficiency confirmation of the lead approaches in larger animal studies and their effect on health outcomes, will shed light on the future direction of this exciting field in combating cancer. Table 1. Summary of Current Methodologies and Nanoparticles used for Cancer Treatment based on the Fenton Reaction

Treatment Method (s)

Nanoparticles

Condition

In Vivo

Ref .


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FR: Fe2+/Fe3+ Fe3O4

Exogenous H2O2: 400 µM

+

56

-

57

+

58

+

61

-

62

+

63

+

64

FR: Fe2+/Fe3+ FeOx-MSN

Exogenous H2O2: 100 µM FR: Fe2+

Amorphous iron

Exogenous H2O2: 50 µM FR: Fe2+/Fe3+

rFeOx-MSN

Exogenous H2O2: 50 µM FR: Fe2+

Fenton based therapy

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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FePt Classical Fenton

Without Exogenous H2O2 FR: Fe2+

FePt@ Graphene oxide

Carrier: Graphene oxide Functionalized with PEG-FA Without Exogenous H2O2 FR: Fe2+

FePt-AuDimercaptosuccinic acid -PEG-FA

Functionalized with PEG-FA Without Exogenous H2O2 FR: Fe2+

SnFe2O4

Without Exogenous H2O2

-

66

rMOF-FA

FR: Fe2+/Fe3+

-

43


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Without Exogenous H2O2 FR: Fe2+/Fe3+ P@rMOF-FA

Without Exogenous H2O2

-

68

-

133

+

70

-

74

+

75

+

76

+

77

Functionalized with PEG-FA Fe2+-containing carbon dots

FR: Fe2+ Without Exogenous H2O2 FR: Mn2+

MSN@MnO2

Without Exogenous H2O2 FR Fe2+

Fe3O4-TAT

Functionalized with TAT peptide 5 Gy radiation FR: Fe2+

Fe2+@MSNlanthanide-doped nanocrystals- Ru2+ Modified Fenton

PhotoFenton

Functionalized Ru2+ 1.0 W/cm2 radiation FR: Fe3+

UCNPsplatinum(IV)ZnFe2O4-PEG

Functionalized: Platinum(IV) and PEG 0.5 W/cm2 radiation

UCNPs@MIL100(Fe)

FR: Fe3+ 0.5 W/cm2 radiation


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SonoFenton

H2O2/Fe3O4-PLGA

FR: Fe2+ 40 MHz sonication

+

55

+

44

+

83

-

90

-

92

+

93

+

46

+

134

+

94

PS: Ce6 FR: Fe3+

MnFe2O4

Carrier: MSN4

O2 production

PS: α-PD-L1 FR: Fe3+

Fe-MOF Photodynami c therapy

Carrier: MOF PS: g-C3N4

Cu+-g-C3N4

FR: Cu+

Synergisti c effects

Fenton for improving traditional methods

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PS: ZnP FR: Fe2+

Bfr-ZnP

Carrier: Bfr PR: FeS2

FeS2-PEG

FR:

Fe2+

PR: Cu2ZnSnS4 FR: Cu2+

Cu2ZnSnS4

Functionalized with BSA Photothermal therapy


PR: Fe3S4 Fe3S4 tetragonal nanosheets

FR: Fe2+/Fe3+ Coated by polyvinylpyrrolido ne PR: Fe3+, Cu2+

Copper ferrite nanospheres

FR: Fe3+, Cu2+ Functionalized with bovine serum albumin


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Drug: β-lapachone FR: Fe2+/Fe3+

Fe3O4@micelles

-

114

-

117

-

51

+

120

+

97

-

100

-

105

+

106

Carrier: Micelles Drug: ascorbic acid Fe3O4@carbon

FR: Fe2+/Fe3+ Functionalized with folic acid Drug: Ascorbic acid FR: Au

Au-MSN- graphene

Carrier: Graphene oxide Functionalized with folic acid

Chemotherap y


L-ascorbyl palmitate/ferrocenemicelles

Drug: L-ascorbyl Palmitate FR: Ferrocene Carrier: Micelles Drug: CA

Ferrocene, CA@micelle

FR: Ferrocene Carrier: Micelles Drug: Dox

Cu2+-Dox- LDHs

FR: Cu2+ Carrier: LDHs Drug: Dox

Cu2+-Dox-MSN

FR: Cu2+ Carrier: MSN

Zirconium-Dox@Pt -Fe3+

Drug: Dox and Platinum


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FR: Fe3+ Carrier: Zr Drug: Dox FR: Fe2+

MSN-Fe-Au

+

107

-

108

+

98

+

122

-

123

-

125

Carrier: MSN Drug: Dox FR: Fe2+ Carrier: MSN Fe3O4@MSN

Functionalized with triphenylphosphoni um, PEG and folic acid

Fe3O4@ PolyethyleniminePt(IV)-PEG

Drug: Cisplatin FR: Fe2+/Fe3+ Carrier: PEG Drug: GOx

GOx- Fe3O4-MSN

FR: Fe2+/Fe3+ Carrier: MSN Drug: GOx

GOx- Fe3O4Hydrogel particle

Catalase -imprinted Fe3O4/Fe@ SiO2/polydopamine

FR: Fe2+/Fe3+ Carrier: Hydrogel particle Drug: Catalase imprinted (SiO2) FR: Fe2+/Fe3+ Carrier: polydopamine


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Drug: 3-amino1,2,4-triazole

Cu–MSN containing 3-amino-1,2,4triazole

FR: Cu2

-

113

+

126

+

127

+

47

+

128

-

129

Carrier: MSN Amorphous iron oxide-RNAi coated with lipid-PEG

Drug: RNAi FR: Fe2+ Carrier: lipid-PEG Drug: DEX-P

FeCl2, DEX-P@ PLGA

FR: Fe2+ Carrier: PLGA Drug: Butyrate

LDH/Butyrate

FR: Ni2+ Carrier: LDH

Drug delivery

Drug: MnCO MnCO-MSN

FR: Mn Carrier: MSN Drug: MnCO

MnCO-MOF

FR: Mn Carrier: MOF

AUTHOR INFORMATION Corresponding Authors Professor Greg Qiao, E-mail: [email protected], Phone: +61383442579, Fax: +61383444153 Professor Dave Dunstan, E-mail: [email protected], Phone: +61383448261, Fax: +61383444153


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ORCID Hadi Ranji-Burachaloo: 0000-0002-2562-8991 Paul A. Gurr: 0000-0001-5246-9845 Dave E. Dunstan: 0000-0002-9931-010X Greg G. Qiao: 0000-0003-2771-9675 ACKNOWLEDGMENT H.R.-B., would like to acknowledge the University of Melbourne for Melbourne International Research Scholarship (MIRS) and the Melbourne International Fee Remission Scholarship (MIFRS). We would also like to thank the Particulate Fluids Processing Centre (PFPC). VOCABULARY cancer therapy, is a method to damage and destroy the cancer cells with less harm to normal cells; chemotherapy, is a type of cancer treatment that uses one or more anti-cancer drugs, photothermal therapy, is a traditional method in which tumor cells are heated by electromagnetic radiation; photodynamic therapy, is another traditional method in which light is used to activate the various photosensitisers to react with molecular oxygen and generate reactive oxygen species; reactive oxygen species, are oxygen-containing molecules such as superoxide anion, radical singlet oxygen and hydrogen peroxide that are required for normal metabolism of all aerobic organisms; Fenton reaction, is a catalytic process to convert hydrogen peroxide into a highly reactive hydroxyl radical.

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Cancer Treatment through Nanoparticle-Facilitated Fenton Reaction

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