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Iron-based nanoparticles and their potential toxicity: Focus on oxidative stress and apoptosis
Chemico-Biological Interactions 316 (2020) 108935
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Iron-based nanoparticles and their potential toxicity: Focus on oxidative stress and apoptosis
T
Jovana Paunovica, Danijela Vucevica, Tatjana Radosavljevica, Stefan Mandić-Rajčevićb,c, Igor Panticd,e,∗ a
Institute of Pathological Physiology, Faculty of Medicine, University of Belgrade, Dr Subotica 9, RS-11129, Belgrade, Serbia School of Public Health and Health Management and Institute of Social Medicine, Faculty of Medicine, University of Belgrade, Serbia c University of Milan and International Centre for Rural Health of the Saints Paolo and Carlo Hospital, 20142, Milan, Italy d Laboratory for cellular physiology, Institute of Medical Physiology, Faculty of Medicine, University of Belgrade, Visegradska 26/II, RS-11129, Belgrade, Serbia e University of Haifa,199 Abba Hushi Blvd. Mount Carmel, Haifa, IL-3498838, Israel b
A R T I C LE I N FO
A B S T R A C T
Keywords: Iron nanoparticles Iron oxide Cytotoxicity Programmed cell death Reactive oxygen species Genotoxicity
Recently, there have been several studies indicating that iron-based nanomaterials may exhibit certain toxic properties. Compared to conventional iron and iron oxides, iron nanoparticles (FeNPs) have some unique physical and chemical traits which impact their absorption, biodistribution and elimination. Facilitated passage through biological barriers enables FeNPs to reach various tissues and cells, and interact with a variety of different compounds. Currently, most of the recent research is focused on the potential cytotoxicity of FeNPs, and its implications on cell viability and functions. Some studies suggested that, in certain cell types, FeNPs may increase levels of oxidative stress and induce generation of reactive oxygen species. Oxidative stress may be one of the most important mechanisms by which FeNPs exhibit cytotoxic effects. Some authors have also suggested that, in certain conditions, exposure to FeNPs, in combination with other factors, may lead to changes in intracellular signaling resulting in programmed cell death. In this short review, we focus on the recent research on potential cytotoxicity of iron-based nanomaterials, and the potential implications of this new knowledge in medicine, chemistry and biology.
1. Introduction Metallic nanoparticles are currently widely used in various areas of industry and engineering. Also, today, many researchers consider metallic nanoparticles to be promising tools for targeted drug delivery, medical imaging, clinical diagnostic and other applications in medicine [1]. Some of the most commonly used metallic nanomaterials for these and other purposes include the ones made of iron, silver, gold, zinc and titanium. Particularly frequently used are iron-based nanoparticles (FeNPs) such as magnetite (Fe3O4) and maghemite (γ-Fe2O3) which have certain superparamagnetic properties making them interesting objects of many areas of contemporary research [2–8]. Various magnetic data storage devices, other devices and instruments used in information technology and engineering, might in the future be designed to include iron nanoparticles. Iron NPs may serve as integral part of different nanowires, nanofibers and coatings [9–11]. Various alloys and catalysts may include iron NPs, either as the main component, or in combination with other advanced materials. Since
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iron nanoparticles have so many potential applications, there is an increased need for evaluation of their potential toxicity [12]. One of the popular applications of nanoscaled iron particles is for decontamination of polluted soil and groundwater [13,14]. Polycyclic aromatic hydrocarbons and halogenated organic compounds may this way be degraded, usually through various mechanisms of chemical reduction. Heavy metals, insecticides and other environmental pollutants may also be transformed/degraded using FeNPs. Contaminant degradation with FeNPs may be much more efficient when compared to traditional micro-scale iron methods, or methods utilizing larger iron particles. Also FeNPs may lead to lower rate of formation of toxic intermediary products during the degradation process. However, during the past several years, some authors have expressed concerns on the potential environmental risk that this application of FeNPs is associated with. Recently, there have been several studies indicating that iron-based nanomaterials may exhibit some toxic properties [3,12,15–19]. Compared to conventional iron and iron oxides, FeNPs have unique
Corresponding author. University of Belgrade, Faculty of Medicine, Visegradska 26/II, RS-11129, Belgrade, Serbia. E-mail address: [email protected] (I. Pantic).
https://doi.org/10.1016/j.cbi.2019.108935 Received 13 December 2019; Accepted 19 December 2019 Available online 21 December 2019 0009-2797/ © 2019 Elsevier B.V. All rights reserved.
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undergo oxidation as the result of contact with water and oxygen. This leads to the formation of oxides such as FeO, α-Fe2O3, γ-Fe2O3 and Fe3O4. Corrosion of zero-valent iron nanoparticles is probably one of the most important chemical transformations that take place in waste waters. For the details regarding the aging of FeNPs and their interactions with oxygen and water, the reader is referred to the recent publication by Lei et al., 2018 [20].
chemical traits which impact their absorption, biodistribution and elimination. Facilitated passage through biological barriers enables FeNPs to reach various tissues and cells, and interact with a variety of different compounds. Currently most research is focused on the potential cytotoxicity of FeNPs, and its implications on cell viability and function. In this short review, we aim to cover recent research of FeNP cytotoxicity in different experimental settings. We primarily focus on the recently published studies on iron-based nanomaterials that are commonly used in industry or as environmental decontaminants, and are therefore most likely to enter and spread through environment.
3. Iron nanoparticles and oxidative stress It seems that reactive oxygen species (ROS) production may be the main mechanism of cell toxicity exhibited by iron-based nanomaterials. Examples of ROS include the reactive oxygen anion superoxide (O2−), hydroxyl radical (neutral form of the hydroxide ion, •OH), and hydrogen peroxide (H2O2). Environmental stress caused by FeNPs may in some cases increase the intracellular production of these compounds. Resulting damage of genetic material or intracellular signaling may lead to reduced cell viability and programmed cell death. In Saccharomyces cerevisiae yeast, α-Fe2O3 nanoparticles may decrease cell viability and proliferation potential. This was demonstrated in a recent study by Zhu et al. (2017) where the authors treated the yeast with 100–600 mg/L NPs for 24 h. Enzyme activity of superoxide dismutase, catalase and glutathione peroxidase (indicators of oxidative stress) was significantly altered which was followed by programmed cell death [28]. Changes in oxidative status were also associated with the reduction of mitochondrial transmembrane potential. There are also some indications that iron oxide nanoparticles (IONPs) may cause mitochondrial oxidative stress, especially in immune cells. In a recent article, Shah et al. (2018) demonstrated that IONPs this way suppress immune function of human T lymphocytes. Changes in mitochondrial structure and function after exposure to IONPs were associated with reduction in proliferation of mitogen-activated T cells, as well as their cytokine production [29]. Potential damage done by IONPs in neural tissue has been linked to oxidative stress. In an article by Yarjanli et al. (2017), the authors give a comprehensive review on recent studies on the role of IONPs on cellular viability in neurodegenerative diseases. It seems that IONPs through ROS generation may damage macromolecules and organelles, and aggregate certain proteins involved in pathogenesis of Alzheimer's and Parkinson's diseases [30]. Iron accumulation, changes in protein function and other mechanisms linked to ROS generation, may cause cell loss and tissue degeneration. It is possible that Fenton and Fenton-like reactions are one of the main mechanisms related to ROS generation by iron nanoparticles [31]:
2. Origin and fate of iron-based nanomaterial in environment There are indeed a number of ways iron-based nanomaterials can reach ecologically sensitive areas. As mentioned before, FeNPs may purposefully be spread in the environment for decontamination of ground water and soil [20,21]. Iron based nanomaterials can this way degrade various potentially dangerous pollutants usually through reduction processes. It is important to state that for this application to be successful, relatively large concentrations of FeNPs may be needed. For example, according to some authors, for an effective field application, the concentration of at least 3 g per liter of zero-valent iron nanoparticles is required [20]. Second, current and future applications in biomedicine increases the probability of FeNPs becoming part of medical waste. Superparamagnetic properties of iron oxide nanoparticles may enable their inclusion into various biosensors, as well as diagnostic agents and therapeutics for targeted drug delivery [22–24]. All these products can relatively easily enter waste waters and contaminate larger regions. Third, various industrial uses of FeNPs and consequent disposal of waste products might lead to the increased presence of these nanoparticles in landfills. At present there are very limited data on the presence and concentration of FeNPs in industrial and community landfills, as well as on the potential interaction of FeNPs and landfill waste materials. The fate of FeNPs in the environment is poorly understood. Like many other metallic nanoparticles, FeNPs have a tendency of homoaggregation increasing the size and surface area, or aggregation with other organic or non-organic compounds with the same effect [20,25,26]. Many different factors may influence the rate of aggregation some of which include environmental acidity, presence of various ions and electrolytes, magnetic properties of the surrounding compounds etc. Also, the initial size and shape of FeNPs are a contributing factor. As a result of aggregation, FeNPs may lose their unique physical and chemical properties and start resembling conventional ionic/elementary iron or iron oxides. It should here be note that FeNPs in many industrial applications are surface coated with various polymers or other substances that provide a certain level of electrosteric stabilization which in turn may reduce the probability of aggregation. It is mostly unknown, how many of these substances interact with environment and to what extent they may prevent aggregation when FeNPs get in contact with waste materials. Interaction of FeNPs with organic colloids is also an important process that takes place when the nanoparticles enter environment [20,27]. These include heteroaggregation with various compounds present on plant cells, bacteria, fungi and viruses. Similarly to homoaggregation, the rate of heteroaggregation depends on many factors, such as size and shape of NPs, concentrations and ratios etc. Despite some efforts, heteroaggregation in waste materials (i.e. interaction with bacteria and fungi present in waste waters) has not yet been sufficiently investigated, and it is crucial to obtain additional info on this issue in order to understand the risk that FeNPs may later pose to living organisms. Finally, FeNPs in environment go through different processes of chemical transformation. These include oxidation, reduction, sulfidation and other modifications. Zero-valent iron nanoparticles (nZVI)
Fe (II) + H2O2 → Fe (III) + OH− + •OH (classic homogeneous Fenton reaction) Fe (II) + H2O2 → Fe (IV) O2+ + H2O (non-radical process) Fe (III) + H2O2 → Fe (II) + HO·2/O2−• + H+ (homogeneous Fentonlike reaction) The Haber-Weiss reaction can also be a significant contributing factor: Fe (III) + HO·2/O2−• → Fe (II) + H2O / OH− + O2 Fe (II) + H2O2 → Fe (III) + OH− + •OH In 2017, Gonzalez-Moragas and associates performed toxicogenomics mechanistic study on the effects of superparamagnetic iron oxide nanoparticles (SPIONs) in nematode Caenorhabditis elegans. The authors did a genome-wide analysis and focused on potential markers of nanotoxicity. The results indicated that the expression of genes involved in oxidative stress is significantly elevated, however, expression of other genes was also quantitatively evaluated. These included genes involved in iron homeostasis, metal detoxification response and endocytosis [32]. 2
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apoptosis). Apoptosis was associated with upregulation of BAX gene expression and downregulation of BCL2 gene expression [38]. In human glioma cells, treatment with iron oxide nanoparticles (goldcoated) may also influence apoptosis process, as demonstrated by Neshastehriz et al. (2018). Although nanoparticles alone did not exhibit significant toxic effects at relatively small doses, they could enhance proapototic effects of hyperthermia/radiation treatment. Apoptosis in this study was evaluated using flow cytometry annexin V–fluorescein isothiocyanate (FITC)/propidium iodide (PI) labeling [39]. As seen from the above text, cytotoxicity and proapoptotic effects of FeNPs (alone or in combination with other factors) may be present in various cancer cells. It is unclear if the same mechanisms by which FeNPs induce apoptosis in tumor cells are taking place in non-malignant cells. It is even unknown if FeNPs have any preference in causing apoptosis in cancer compared to normal cells. Additional research is needed in the future in order to give us better insight on the potential applicability of FeNPs in the areas of oncology and cancer research.
However, it should be stressed that not all authors agree with the above mentioned findings on FeNP-induced cytotoxicity mediated by oxidative stress. Some studies have even indicated potential protective effects of FeNPs. For example, in plants, it seems that FeNPs in certain doses (seeds primed with FeNPs 5, 10, 15, and 20 mg/L) have positive effects on plant height, weight and photosynthesis process [33]. Also in cadmium treated plats (cadmium used as toxin), FeNPs may decrease superoxide dismutase and peroxidase activities as well as electrolyte loss. Taking all of these data into account, one could say that the generation of ROS may indeed be one of the main causes of FeNP-related cytotoxicity. However, there is still a considerable lack of high quality studies that demonstrate this phenomena, and further investigation is required. Before more extensive research is performed on this issue, one should avoid making definite conclusions on the toxic effects exhibited by FeNPs. 4. Iron nanoparticles and apoptosis
5. Future research on the toxicity of iron-based nanomaterials Programmed cell death (apoptosis) may be one of the possible outcomes of prolonged damage caused by external toxins. Apoptosis usually take place when the cell is unable to repair DNA alterations and/or when a specific intracellular signaling pathway is activated. This is the reason why many studies focused on oxidative stress and ROS generation at the same time investigate apoptosis. Free radicals have in some cases the ability to damage cell nucleus in a way that initiates this sort of proapoptotic signals. Early stages of apoptosis usually include significant changes in chromatin organization and distribution. For example, chromatin may become more condensed and marginalized. The study performed by Zhu et al. (2010) observed apoptotic chromatin condensation in cultured human umbilical endothelial cells after treatment with iron oxide nanoparticles. This was associated with the loss of mitochondria membrane potential and increased production of nitric oxide [34]. Superparamagnetic iron oxide nanoparticle may also induce apoptosis in neuronal cells. In a recent research, Liu et al. (2018) showed that in dopaminergic neuronal PC12 cells, treatment with superparamagnetic iron oxide nanoparticles this way reduce cell viability, but also have other detrimental effects, such as the loss of the ability of the neurons to extend neurites in response to nerve growth factor [35]. These results were also confirmed in in vivo experiment, after injecting nanoparticles in mouse dorsal striatum or hippocampus. It was concluded that nanoparticles may decrease nere fiber density in these brain regions. In certain cell lines, autophagy may precede apoptosis after FeNP treatment. Autophagy (or autophagocytosis) is a closely regulated process in which damaged or excess organelles are digested and recycled. It can be activated by various toxins, but also as the result of changes in intracellular signaling during many physiological events. The group of Korean researchers in 2014, found that magnetic iron oxide nanoparticles in murine peritoneal macrophage cell line, may cause autophagy, possibly as a result of mitochondrial dysfunction and endoplasmic reticulum stress [36]. Apoptosis occurred only after autophagy took place, and it seems that autolysosome formation might have a significant role in this sequence of events. There are several signaling pathways that may be involved in FeNPinduced apoptosis. For example, in some cancer cells, p53, - Bax/Bad and Bcl2 - associated signaling may be one of the most important mechanisms. In a recent work by Wang et al. (2017) it was suggested that in non-small-cell lung cancer cells, iron oxide (Fe3O4) magnetic nanoparticles in combination with actein, may activate the caspase 3signaling pathway and inhibit antiapoptotic proteins Bcl2 and BclXL. This may be followed by upregulation of proapoptotic proteins Bax and Bad [37]. In another study done by Jalili et al. (2016), in human breast cancer cells, combination of FeNPs with cold atmospheric plasma reduced cell viability and increased annexin-V labeling (marker of
As mentioned before, many issues related to FeNP cytotoxicity remain unclear, and extensive future research will be required in order to clarify them. At present, there aren't many high quality studies in which cell viability, apoptosis and intracellular ROS generation are tested after FeNP exposure. Therefore, one cannot be certain even if FeNPs are at all toxic, and, presently, no conclusive recommendations can be made on their use and potential health risk. In the future, additional studies will need to be performed to clarify the rate of intracellular and extracellular transformation of FeNPs to iron ions and larger particles of iron (diameter larger than 100 nm). In other words, at present, we are unsure of the tendency of iron nanoparticles to aggregate to larger particles or transform to other iron forms when they reach and/or enter the cell [40]. When we observe phenomena such as oxidative stress or apoptosis, in many cases we cannot be sure if they occur due to FeNPs, or Fe particles (and compounds) of much larger size. With current level of technology and contemporary methods, it is unfortunately very difficult (but not impossible) to successfully perform research of this complexity and magnitude and obtain useful results. Second, it should be noted that not all FeNPs are same in terms of their size, shape, surface area, charge and other parameters. For example, FeNPs of 10 nm in diameter compared to the ones sized 90 nm, probably have different physical and chemical characteristics, which in turn imply that their biological effects significantly differ. It is quite possible that some FeNPs exhibit cytotoxicity while others are relatively safe. Third, there is a considerable lack of research focused on morphological effects of FeNPs in cells and tissues. It is, for example, unknown to what extent FeNPs change chromatin architecture and distribution in cell nucleus. Also, the impact of FeNPs on cell communication, migration and tissue architecture is unknown. Detailed histological evaluation, using various methods of optical and electron microscopy will be required to supplement the research on FeNPs cytotoxicity. Some studies have already started with application of contemporary microscopy methods to quantify cellular effects of FeNPs. For example the recent study done by our laboratory focused on fractal analysis of cell nuclei (optical micrographs) after treatment with iron oxide nanoparticles [16]. It was concluded that the NPs decrease nuclear fractal dimension (indicator of mathematical complexity) in a time-dependent manner. Our current research is focused on the potential impact of iron oxide nanoparticles on liver cell (hepathocyte) chromatin mathematical organization. Preliminary results indicate that FeNPs indeed change certain textural and wavelet chromatin parameters in mice. Application of these and other mathematical and computational methods will provide us with additional knowledge on possible detrimental FeNP effects on different cells in physiological conditions. 3
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In conclusion, current data on the potential cytotoxicity of ironbased nanomaterials are very limited. Some studies suggested that, in certain cell types FeNPs increase levels of oxidative stress and induce generation of reactive oxygen species. Oxidative stress may be one of the most important mechanisms by which FeNPs exhibit cytotoxic effects. Some authors have also suggested that, in certain conditions, exposure to FeNPs, in combination with other factors, may lead to changes in intracellular signaling resulting in programmed cell death. One should however be cautious when interpreting these results since the overall number of high-quality studies investigating these issues is relatively low. Hopefully, in the future, more extensive research will be performed and we will be able to draw definite conclusions on the cytotoxicity of iron-based nanomaterials.
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Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Acknowledgements The authors are grateful to the the projects of the Ministry of Education and Science, Republic of Serbia (projects OI-175015, OI175059, III-41027 and TR-37001). Prof. Igor Pantic is also grateful to NSF Center for Advanced Knowledge Enablement, Miami, FL, USA (I. Pantic is an external research associate). References [1] R. Dinali, A. Ebrahiminezhad, M. Manley-Harris, Y. Ghasemi, A. Berenjian, Iron oxide nanoparticles in modern microbiology and biotechnology, Crit. Rev. Microbiol. 43 (2017) 493–507. [2] J. Dulinska-Litewka, A. Lazarczyk, P. Halubiec, O. Szafranski, K. Karnas, A. Karewicz, Superparamagnetic Iron Oxide Nanoparticles-Current and Prospective Medical Applications, Materials, (2019), p. 12. [3] J. Hurtado-Gallego, G. Pulido-Reyes, M. Gonzalez-Pleiter, G. Salas, F. Leganes, R. Rosal, F. Fernandez-Pinas, Toxicity of superparamagnetic iron oxide nanoparticles to the microalga Chlamydomonas reinhardtii, Chemosphere 238 (2020) 124562. [4] L. Jie, D. Lang, X. Kang, Z. Yang, Y. Du, X. Ying, Superparamagnetic iron oxide nanoparticles/doxorubicin-loaded starch-octanoic micelles for targeted tumor therapy, J. Nanosci. Nanotechnol. 19 (2019) 5456–5462. [5] C. Shen, X. Wang, Z. Zheng, C. Gao, X. Chen, S. Zhao, Z. Dai, Doxorubicin and indocyanine green loaded superparamagnetic iron oxide nanoparticles with PEGylated phospholipid coating for magnetic resonance with fluorescence imaging and chemotherapy of glioma, Int. J. Nanomed. 14 (2019) 101–117. [6] B. Wang, O. Sandre, K. Wang, H. Shi, K. Xiong, Y.B. Huang, T. Wu, M. Yan, J. Courtois, Auto-degradable and biocompatible superparamagnetic iron oxide nanoparticles/polypeptides colloidal polyion complexes with high density of magnetic material, Materials science & engineering, C, Materials for biological applications 104 (2019) 109920. [7] L. Xie, W. Jin, H. Chen, Q. Zhang, Superparamagnetic iron oxide nanoparticles for cancer diagnosis and therapy, J. Biomed. Nanotechnol. 15 (2019) 215–416. [8] L. Zhang, R. Jin, R. Sun, L. Du, L. Liu, K. Zhang, H. Ai, Y. Guo, Superparamagnetic iron oxide nanoparticles as magnetic resonance imaging contrast agents and induced autophagy response in endothelial progenitor cells, J. Biomed. Nanotechnol. 15 (2019) 396–404. [9] R.A. Bennett, H.A. Etman, H. Hicks, L. Richards, C. Wu, M.R. Castell, S.S. Dhesi, F. Maccherozzi, Magnetic iron oxide nanowires formed by reactive dewetting, Nano Lett. 18 (2018) 2365–2372. [10] C. Gu, S. Hu, X. Zheng, M.R. Gao, Y.R. Zheng, L. Shi, Q. Gao, X. Zheng, W. Chu, H.B. Yao, J. Zhu, S.H. Yu, Synthesis of sub-2 nm iron-doped NiSe2 nanowires and their surface-confined oxidation for oxygen evolution catalysis, Angew. Chem. 57 (2018) 4020–4024. [11] A.I. Martinez Banderas, A. Aires, M. Quintanilla, J.A. Holguin-Lerma, C. LozanoPedraza, F.J. Teran, J. Moreno, J.E. Perez, B.S. Ooi, T. Ravasi, J.S. Merzaban, A.L. Cortajarena, J. Kosel, Iron-Based Core-Shell Nanowires for Combinatorial Drug Delivery, Photothermal and Magnetic Therapy, ACS applied materials & interfaces, 2019. [12] V. Valdiglesias, N. Fernandez-Bertolez, G. Kilic, C. Costa, S. Costa, S. Fraga, M.J. Bessa, E. Pasaro, J.P. Teixeira, B. Laffon, Are iron oxide nanoparticles safe? Current knowledge and future perspectives, J. Trace Elem. Med. Biol. : organ of the Society for Minerals and Trace Elements 38 (2016) 53–63. [13] A.M. Gutierrez, T.D. Dziubla, J.Z. Hilt, Recent advances on iron oxide magnetic nanoparticles as sorbents of organic pollutants in water and wastewater treatment,
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Iron-based nanoparticles and their potential toxicity: Focus on oxidative stress and apoptosis
T
Jovana Paunovica, Danijela Vucevica, Tatjana Radosavljevica, Stefan Mandić-Rajčevićb,c, Igor Panticd,e,∗ a
Institute of Pathological Physiology, Faculty of Medicine, University of Belgrade, Dr Subotica 9, RS-11129, Belgrade, Serbia School of Public Health and Health Management and Institute of Social Medicine, Faculty of Medicine, University of Belgrade, Serbia c University of Milan and International Centre for Rural Health of the Saints Paolo and Carlo Hospital, 20142, Milan, Italy d Laboratory for cellular physiology, Institute of Medical Physiology, Faculty of Medicine, University of Belgrade, Visegradska 26/II, RS-11129, Belgrade, Serbia e University of Haifa,199 Abba Hushi Blvd. Mount Carmel, Haifa, IL-3498838, Israel b
A R T I C LE I N FO
A B S T R A C T
Keywords: Iron nanoparticles Iron oxide Cytotoxicity Programmed cell death Reactive oxygen species Genotoxicity
Recently, there have been several studies indicating that iron-based nanomaterials may exhibit certain toxic properties. Compared to conventional iron and iron oxides, iron nanoparticles (FeNPs) have some unique physical and chemical traits which impact their absorption, biodistribution and elimination. Facilitated passage through biological barriers enables FeNPs to reach various tissues and cells, and interact with a variety of different compounds. Currently, most of the recent research is focused on the potential cytotoxicity of FeNPs, and its implications on cell viability and functions. Some studies suggested that, in certain cell types, FeNPs may increase levels of oxidative stress and induce generation of reactive oxygen species. Oxidative stress may be one of the most important mechanisms by which FeNPs exhibit cytotoxic effects. Some authors have also suggested that, in certain conditions, exposure to FeNPs, in combination with other factors, may lead to changes in intracellular signaling resulting in programmed cell death. In this short review, we focus on the recent research on potential cytotoxicity of iron-based nanomaterials, and the potential implications of this new knowledge in medicine, chemistry and biology.
1. Introduction Metallic nanoparticles are currently widely used in various areas of industry and engineering. Also, today, many researchers consider metallic nanoparticles to be promising tools for targeted drug delivery, medical imaging, clinical diagnostic and other applications in medicine [1]. Some of the most commonly used metallic nanomaterials for these and other purposes include the ones made of iron, silver, gold, zinc and titanium. Particularly frequently used are iron-based nanoparticles (FeNPs) such as magnetite (Fe3O4) and maghemite (γ-Fe2O3) which have certain superparamagnetic properties making them interesting objects of many areas of contemporary research [2–8]. Various magnetic data storage devices, other devices and instruments used in information technology and engineering, might in the future be designed to include iron nanoparticles. Iron NPs may serve as integral part of different nanowires, nanofibers and coatings [9–11]. Various alloys and catalysts may include iron NPs, either as the main component, or in combination with other advanced materials. Since
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iron nanoparticles have so many potential applications, there is an increased need for evaluation of their potential toxicity [12]. One of the popular applications of nanoscaled iron particles is for decontamination of polluted soil and groundwater [13,14]. Polycyclic aromatic hydrocarbons and halogenated organic compounds may this way be degraded, usually through various mechanisms of chemical reduction. Heavy metals, insecticides and other environmental pollutants may also be transformed/degraded using FeNPs. Contaminant degradation with FeNPs may be much more efficient when compared to traditional micro-scale iron methods, or methods utilizing larger iron particles. Also FeNPs may lead to lower rate of formation of toxic intermediary products during the degradation process. However, during the past several years, some authors have expressed concerns on the potential environmental risk that this application of FeNPs is associated with. Recently, there have been several studies indicating that iron-based nanomaterials may exhibit some toxic properties [3,12,15–19]. Compared to conventional iron and iron oxides, FeNPs have unique
Corresponding author. University of Belgrade, Faculty of Medicine, Visegradska 26/II, RS-11129, Belgrade, Serbia. E-mail address: [email protected] (I. Pantic).
https://doi.org/10.1016/j.cbi.2019.108935 Received 13 December 2019; Accepted 19 December 2019 Available online 21 December 2019 0009-2797/ © 2019 Elsevier B.V. All rights reserved.
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undergo oxidation as the result of contact with water and oxygen. This leads to the formation of oxides such as FeO, α-Fe2O3, γ-Fe2O3 and Fe3O4. Corrosion of zero-valent iron nanoparticles is probably one of the most important chemical transformations that take place in waste waters. For the details regarding the aging of FeNPs and their interactions with oxygen and water, the reader is referred to the recent publication by Lei et al., 2018 [20].
chemical traits which impact their absorption, biodistribution and elimination. Facilitated passage through biological barriers enables FeNPs to reach various tissues and cells, and interact with a variety of different compounds. Currently most research is focused on the potential cytotoxicity of FeNPs, and its implications on cell viability and function. In this short review, we aim to cover recent research of FeNP cytotoxicity in different experimental settings. We primarily focus on the recently published studies on iron-based nanomaterials that are commonly used in industry or as environmental decontaminants, and are therefore most likely to enter and spread through environment.
3. Iron nanoparticles and oxidative stress It seems that reactive oxygen species (ROS) production may be the main mechanism of cell toxicity exhibited by iron-based nanomaterials. Examples of ROS include the reactive oxygen anion superoxide (O2−), hydroxyl radical (neutral form of the hydroxide ion, •OH), and hydrogen peroxide (H2O2). Environmental stress caused by FeNPs may in some cases increase the intracellular production of these compounds. Resulting damage of genetic material or intracellular signaling may lead to reduced cell viability and programmed cell death. In Saccharomyces cerevisiae yeast, α-Fe2O3 nanoparticles may decrease cell viability and proliferation potential. This was demonstrated in a recent study by Zhu et al. (2017) where the authors treated the yeast with 100–600 mg/L NPs for 24 h. Enzyme activity of superoxide dismutase, catalase and glutathione peroxidase (indicators of oxidative stress) was significantly altered which was followed by programmed cell death [28]. Changes in oxidative status were also associated with the reduction of mitochondrial transmembrane potential. There are also some indications that iron oxide nanoparticles (IONPs) may cause mitochondrial oxidative stress, especially in immune cells. In a recent article, Shah et al. (2018) demonstrated that IONPs this way suppress immune function of human T lymphocytes. Changes in mitochondrial structure and function after exposure to IONPs were associated with reduction in proliferation of mitogen-activated T cells, as well as their cytokine production [29]. Potential damage done by IONPs in neural tissue has been linked to oxidative stress. In an article by Yarjanli et al. (2017), the authors give a comprehensive review on recent studies on the role of IONPs on cellular viability in neurodegenerative diseases. It seems that IONPs through ROS generation may damage macromolecules and organelles, and aggregate certain proteins involved in pathogenesis of Alzheimer's and Parkinson's diseases [30]. Iron accumulation, changes in protein function and other mechanisms linked to ROS generation, may cause cell loss and tissue degeneration. It is possible that Fenton and Fenton-like reactions are one of the main mechanisms related to ROS generation by iron nanoparticles [31]:
2. Origin and fate of iron-based nanomaterial in environment There are indeed a number of ways iron-based nanomaterials can reach ecologically sensitive areas. As mentioned before, FeNPs may purposefully be spread in the environment for decontamination of ground water and soil [20,21]. Iron based nanomaterials can this way degrade various potentially dangerous pollutants usually through reduction processes. It is important to state that for this application to be successful, relatively large concentrations of FeNPs may be needed. For example, according to some authors, for an effective field application, the concentration of at least 3 g per liter of zero-valent iron nanoparticles is required [20]. Second, current and future applications in biomedicine increases the probability of FeNPs becoming part of medical waste. Superparamagnetic properties of iron oxide nanoparticles may enable their inclusion into various biosensors, as well as diagnostic agents and therapeutics for targeted drug delivery [22–24]. All these products can relatively easily enter waste waters and contaminate larger regions. Third, various industrial uses of FeNPs and consequent disposal of waste products might lead to the increased presence of these nanoparticles in landfills. At present there are very limited data on the presence and concentration of FeNPs in industrial and community landfills, as well as on the potential interaction of FeNPs and landfill waste materials. The fate of FeNPs in the environment is poorly understood. Like many other metallic nanoparticles, FeNPs have a tendency of homoaggregation increasing the size and surface area, or aggregation with other organic or non-organic compounds with the same effect [20,25,26]. Many different factors may influence the rate of aggregation some of which include environmental acidity, presence of various ions and electrolytes, magnetic properties of the surrounding compounds etc. Also, the initial size and shape of FeNPs are a contributing factor. As a result of aggregation, FeNPs may lose their unique physical and chemical properties and start resembling conventional ionic/elementary iron or iron oxides. It should here be note that FeNPs in many industrial applications are surface coated with various polymers or other substances that provide a certain level of electrosteric stabilization which in turn may reduce the probability of aggregation. It is mostly unknown, how many of these substances interact with environment and to what extent they may prevent aggregation when FeNPs get in contact with waste materials. Interaction of FeNPs with organic colloids is also an important process that takes place when the nanoparticles enter environment [20,27]. These include heteroaggregation with various compounds present on plant cells, bacteria, fungi and viruses. Similarly to homoaggregation, the rate of heteroaggregation depends on many factors, such as size and shape of NPs, concentrations and ratios etc. Despite some efforts, heteroaggregation in waste materials (i.e. interaction with bacteria and fungi present in waste waters) has not yet been sufficiently investigated, and it is crucial to obtain additional info on this issue in order to understand the risk that FeNPs may later pose to living organisms. Finally, FeNPs in environment go through different processes of chemical transformation. These include oxidation, reduction, sulfidation and other modifications. Zero-valent iron nanoparticles (nZVI)
Fe (II) + H2O2 → Fe (III) + OH− + •OH (classic homogeneous Fenton reaction) Fe (II) + H2O2 → Fe (IV) O2+ + H2O (non-radical process) Fe (III) + H2O2 → Fe (II) + HO·2/O2−• + H+ (homogeneous Fentonlike reaction) The Haber-Weiss reaction can also be a significant contributing factor: Fe (III) + HO·2/O2−• → Fe (II) + H2O / OH− + O2 Fe (II) + H2O2 → Fe (III) + OH− + •OH In 2017, Gonzalez-Moragas and associates performed toxicogenomics mechanistic study on the effects of superparamagnetic iron oxide nanoparticles (SPIONs) in nematode Caenorhabditis elegans. The authors did a genome-wide analysis and focused on potential markers of nanotoxicity. The results indicated that the expression of genes involved in oxidative stress is significantly elevated, however, expression of other genes was also quantitatively evaluated. These included genes involved in iron homeostasis, metal detoxification response and endocytosis [32]. 2
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apoptosis). Apoptosis was associated with upregulation of BAX gene expression and downregulation of BCL2 gene expression [38]. In human glioma cells, treatment with iron oxide nanoparticles (goldcoated) may also influence apoptosis process, as demonstrated by Neshastehriz et al. (2018). Although nanoparticles alone did not exhibit significant toxic effects at relatively small doses, they could enhance proapototic effects of hyperthermia/radiation treatment. Apoptosis in this study was evaluated using flow cytometry annexin V–fluorescein isothiocyanate (FITC)/propidium iodide (PI) labeling [39]. As seen from the above text, cytotoxicity and proapoptotic effects of FeNPs (alone or in combination with other factors) may be present in various cancer cells. It is unclear if the same mechanisms by which FeNPs induce apoptosis in tumor cells are taking place in non-malignant cells. It is even unknown if FeNPs have any preference in causing apoptosis in cancer compared to normal cells. Additional research is needed in the future in order to give us better insight on the potential applicability of FeNPs in the areas of oncology and cancer research.
However, it should be stressed that not all authors agree with the above mentioned findings on FeNP-induced cytotoxicity mediated by oxidative stress. Some studies have even indicated potential protective effects of FeNPs. For example, in plants, it seems that FeNPs in certain doses (seeds primed with FeNPs 5, 10, 15, and 20 mg/L) have positive effects on plant height, weight and photosynthesis process [33]. Also in cadmium treated plats (cadmium used as toxin), FeNPs may decrease superoxide dismutase and peroxidase activities as well as electrolyte loss. Taking all of these data into account, one could say that the generation of ROS may indeed be one of the main causes of FeNP-related cytotoxicity. However, there is still a considerable lack of high quality studies that demonstrate this phenomena, and further investigation is required. Before more extensive research is performed on this issue, one should avoid making definite conclusions on the toxic effects exhibited by FeNPs. 4. Iron nanoparticles and apoptosis
5. Future research on the toxicity of iron-based nanomaterials Programmed cell death (apoptosis) may be one of the possible outcomes of prolonged damage caused by external toxins. Apoptosis usually take place when the cell is unable to repair DNA alterations and/or when a specific intracellular signaling pathway is activated. This is the reason why many studies focused on oxidative stress and ROS generation at the same time investigate apoptosis. Free radicals have in some cases the ability to damage cell nucleus in a way that initiates this sort of proapoptotic signals. Early stages of apoptosis usually include significant changes in chromatin organization and distribution. For example, chromatin may become more condensed and marginalized. The study performed by Zhu et al. (2010) observed apoptotic chromatin condensation in cultured human umbilical endothelial cells after treatment with iron oxide nanoparticles. This was associated with the loss of mitochondria membrane potential and increased production of nitric oxide [34]. Superparamagnetic iron oxide nanoparticle may also induce apoptosis in neuronal cells. In a recent research, Liu et al. (2018) showed that in dopaminergic neuronal PC12 cells, treatment with superparamagnetic iron oxide nanoparticles this way reduce cell viability, but also have other detrimental effects, such as the loss of the ability of the neurons to extend neurites in response to nerve growth factor [35]. These results were also confirmed in in vivo experiment, after injecting nanoparticles in mouse dorsal striatum or hippocampus. It was concluded that nanoparticles may decrease nere fiber density in these brain regions. In certain cell lines, autophagy may precede apoptosis after FeNP treatment. Autophagy (or autophagocytosis) is a closely regulated process in which damaged or excess organelles are digested and recycled. It can be activated by various toxins, but also as the result of changes in intracellular signaling during many physiological events. The group of Korean researchers in 2014, found that magnetic iron oxide nanoparticles in murine peritoneal macrophage cell line, may cause autophagy, possibly as a result of mitochondrial dysfunction and endoplasmic reticulum stress [36]. Apoptosis occurred only after autophagy took place, and it seems that autolysosome formation might have a significant role in this sequence of events. There are several signaling pathways that may be involved in FeNPinduced apoptosis. For example, in some cancer cells, p53, - Bax/Bad and Bcl2 - associated signaling may be one of the most important mechanisms. In a recent work by Wang et al. (2017) it was suggested that in non-small-cell lung cancer cells, iron oxide (Fe3O4) magnetic nanoparticles in combination with actein, may activate the caspase 3signaling pathway and inhibit antiapoptotic proteins Bcl2 and BclXL. This may be followed by upregulation of proapoptotic proteins Bax and Bad [37]. In another study done by Jalili et al. (2016), in human breast cancer cells, combination of FeNPs with cold atmospheric plasma reduced cell viability and increased annexin-V labeling (marker of
As mentioned before, many issues related to FeNP cytotoxicity remain unclear, and extensive future research will be required in order to clarify them. At present, there aren't many high quality studies in which cell viability, apoptosis and intracellular ROS generation are tested after FeNP exposure. Therefore, one cannot be certain even if FeNPs are at all toxic, and, presently, no conclusive recommendations can be made on their use and potential health risk. In the future, additional studies will need to be performed to clarify the rate of intracellular and extracellular transformation of FeNPs to iron ions and larger particles of iron (diameter larger than 100 nm). In other words, at present, we are unsure of the tendency of iron nanoparticles to aggregate to larger particles or transform to other iron forms when they reach and/or enter the cell [40]. When we observe phenomena such as oxidative stress or apoptosis, in many cases we cannot be sure if they occur due to FeNPs, or Fe particles (and compounds) of much larger size. With current level of technology and contemporary methods, it is unfortunately very difficult (but not impossible) to successfully perform research of this complexity and magnitude and obtain useful results. Second, it should be noted that not all FeNPs are same in terms of their size, shape, surface area, charge and other parameters. For example, FeNPs of 10 nm in diameter compared to the ones sized 90 nm, probably have different physical and chemical characteristics, which in turn imply that their biological effects significantly differ. It is quite possible that some FeNPs exhibit cytotoxicity while others are relatively safe. Third, there is a considerable lack of research focused on morphological effects of FeNPs in cells and tissues. It is, for example, unknown to what extent FeNPs change chromatin architecture and distribution in cell nucleus. Also, the impact of FeNPs on cell communication, migration and tissue architecture is unknown. Detailed histological evaluation, using various methods of optical and electron microscopy will be required to supplement the research on FeNPs cytotoxicity. Some studies have already started with application of contemporary microscopy methods to quantify cellular effects of FeNPs. For example the recent study done by our laboratory focused on fractal analysis of cell nuclei (optical micrographs) after treatment with iron oxide nanoparticles [16]. It was concluded that the NPs decrease nuclear fractal dimension (indicator of mathematical complexity) in a time-dependent manner. Our current research is focused on the potential impact of iron oxide nanoparticles on liver cell (hepathocyte) chromatin mathematical organization. Preliminary results indicate that FeNPs indeed change certain textural and wavelet chromatin parameters in mice. Application of these and other mathematical and computational methods will provide us with additional knowledge on possible detrimental FeNP effects on different cells in physiological conditions. 3
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In conclusion, current data on the potential cytotoxicity of ironbased nanomaterials are very limited. Some studies suggested that, in certain cell types FeNPs increase levels of oxidative stress and induce generation of reactive oxygen species. Oxidative stress may be one of the most important mechanisms by which FeNPs exhibit cytotoxic effects. Some authors have also suggested that, in certain conditions, exposure to FeNPs, in combination with other factors, may lead to changes in intracellular signaling resulting in programmed cell death. One should however be cautious when interpreting these results since the overall number of high-quality studies investigating these issues is relatively low. Hopefully, in the future, more extensive research will be performed and we will be able to draw definite conclusions on the cytotoxicity of iron-based nanomaterials.
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Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Acknowledgements The authors are grateful to the the projects of the Ministry of Education and Science, Republic of Serbia (projects OI-175015, OI175059, III-41027 and TR-37001). Prof. Igor Pantic is also grateful to NSF Center for Advanced Knowledge Enablement, Miami, FL, USA (I. Pantic is an external research associate). References [1] R. Dinali, A. Ebrahiminezhad, M. Manley-Harris, Y. Ghasemi, A. Berenjian, Iron oxide nanoparticles in modern microbiology and biotechnology, Crit. Rev. Microbiol. 43 (2017) 493–507. [2] J. Dulinska-Litewka, A. Lazarczyk, P. Halubiec, O. Szafranski, K. Karnas, A. Karewicz, Superparamagnetic Iron Oxide Nanoparticles-Current and Prospective Medical Applications, Materials, (2019), p. 12. [3] J. Hurtado-Gallego, G. Pulido-Reyes, M. Gonzalez-Pleiter, G. Salas, F. Leganes, R. Rosal, F. Fernandez-Pinas, Toxicity of superparamagnetic iron oxide nanoparticles to the microalga Chlamydomonas reinhardtii, Chemosphere 238 (2020) 124562. [4] L. Jie, D. Lang, X. Kang, Z. Yang, Y. Du, X. Ying, Superparamagnetic iron oxide nanoparticles/doxorubicin-loaded starch-octanoic micelles for targeted tumor therapy, J. Nanosci. Nanotechnol. 19 (2019) 5456–5462. [5] C. Shen, X. Wang, Z. Zheng, C. Gao, X. Chen, S. Zhao, Z. Dai, Doxorubicin and indocyanine green loaded superparamagnetic iron oxide nanoparticles with PEGylated phospholipid coating for magnetic resonance with fluorescence imaging and chemotherapy of glioma, Int. J. Nanomed. 14 (2019) 101–117. [6] B. Wang, O. Sandre, K. Wang, H. Shi, K. Xiong, Y.B. Huang, T. Wu, M. Yan, J. Courtois, Auto-degradable and biocompatible superparamagnetic iron oxide nanoparticles/polypeptides colloidal polyion complexes with high density of magnetic material, Materials science & engineering, C, Materials for biological applications 104 (2019) 109920. [7] L. Xie, W. Jin, H. Chen, Q. Zhang, Superparamagnetic iron oxide nanoparticles for cancer diagnosis and therapy, J. Biomed. Nanotechnol. 15 (2019) 215–416. [8] L. Zhang, R. Jin, R. Sun, L. Du, L. Liu, K. Zhang, H. Ai, Y. Guo, Superparamagnetic iron oxide nanoparticles as magnetic resonance imaging contrast agents and induced autophagy response in endothelial progenitor cells, J. Biomed. Nanotechnol. 15 (2019) 396–404. [9] R.A. Bennett, H.A. Etman, H. Hicks, L. Richards, C. Wu, M.R. Castell, S.S. Dhesi, F. Maccherozzi, Magnetic iron oxide nanowires formed by reactive dewetting, Nano Lett. 18 (2018) 2365–2372. [10] C. Gu, S. Hu, X. Zheng, M.R. Gao, Y.R. Zheng, L. Shi, Q. Gao, X. Zheng, W. Chu, H.B. Yao, J. Zhu, S.H. Yu, Synthesis of sub-2 nm iron-doped NiSe2 nanowires and their surface-confined oxidation for oxygen evolution catalysis, Angew. Chem. 57 (2018) 4020–4024. [11] A.I. Martinez Banderas, A. Aires, M. Quintanilla, J.A. Holguin-Lerma, C. LozanoPedraza, F.J. Teran, J. Moreno, J.E. Perez, B.S. Ooi, T. Ravasi, J.S. Merzaban, A.L. Cortajarena, J. Kosel, Iron-Based Core-Shell Nanowires for Combinatorial Drug Delivery, Photothermal and Magnetic Therapy, ACS applied materials & interfaces, 2019. [12] V. Valdiglesias, N. Fernandez-Bertolez, G. Kilic, C. Costa, S. Costa, S. Fraga, M.J. Bessa, E. Pasaro, J.P. Teixeira, B. Laffon, Are iron oxide nanoparticles safe? Current knowledge and future perspectives, J. Trace Elem. Med. Biol. : organ of the Society for Minerals and Trace Elements 38 (2016) 53–63. [13] A.M. Gutierrez, T.D. Dziubla, J.Z. Hilt, Recent advances on iron oxide magnetic nanoparticles as sorbents of organic pollutants in water and wastewater treatment,
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