Are iron oxide nanoparticles safe? Current knowledge and future perspectives
Introduction
Nanotechnology is rapidly expanding. With the increased applications of nanotechnology products, especially for biomedical purposes, concerns regarding the onset of unexpected adverse health effects following exposure have been also raised. Understanding of toxicological profiles of engineered nanomaterials is necessary in order to ensure that these materials are safe for use and are developed responsibly, with optimization of benefits and minimization of risks. However, development and production of engineered nanomaterials are increasing faster than generation of toxicological information. This lack of information on possible adverse effects of nanomaterials has been taken into consideration by many organizations worldwide such as the US Environmental Protection Agency (EPA), the World Health Organization (WHO), the US National Institute for Occupational Safety and Health (NIOSH), the European Commission (EC) and the Organization for Economic Co-operation and Development (OECD). Official documents have been prepared by these organizations addressing the need of dedicated research on appropriate methodological assays for assessing engineered nanomaterials toxicity [1]. Consequently, starting in the early 2000s, concerns about the potential human and environmental health effects of nanomaterials were being expressed by many scientists, regulators, and non-governmental agencies. Indeed, as a proof of the growing interest on this topic, the number of scientific articles published on ‘nanotoxicity’ or ‘nanotoxicology’ increased progressively in the last decade (around 1700 so far, according to PubMed database); before 2005 it was almost negligible.
Among engineered nanomaterials magnetic nanoparticles – made of iron, cobalt, or nickel oxides – offer promising possibilities in biomedical field mainly due to their special physicochemical features, including their proven biocompatibility and their magnetic properties that allow them to be manipulated by an external magnetic field gradient [2]. Particularly, nanoparticles made of a ferro- or ferromagnetic material, i.e., iron oxide nanoparticles (ION), can exhibit a unique form of magnetism called superparamagnetism, which appears when the ION size is below a critical value – depending on the material, but typically around 10–20 nm –, and when the temperature is above the so-called blocking temperature [3]. This superparamagnetic behaviour is highly useful in biomedicine for a number of applications mainly related to diagnosis, tumour imaging, imaging of the central nervous system for neurovascular, neurooncological or neuroinflammatory processes, and drug delivery [4], [5]. Indeed, clinical use of several ION as contrast agents for imaging were already approved by the US Food and Drug Administration since 1996 (US FDA) [6], [7], [8]. Therefore, due to the current and promising biomedical uses of ION involving the direct contact with different tissues and organs, studies addressing their potential toxicity are especially relevant.
ION are usually made of a crystalline core and a surface coating for stabilizing the core properties and optionally for preventing the aggregation. The crystalline core of ION, made of ferri- (Fe3+) or ferro- (Fe2+) magnetic material, is generally synthesized through protocols with controlled precipitation of iron oxides in organic solution [9], or in aqueous solution by adding a base [10]. Among the eight iron oxides known, magnetite (Fe3O4), maghemite (γ-Fe2O3) and hematite (α-Fe2O3) are the most commonly used due to their polymorphism involving temperature-induced phase transition; they have unique biochemical, magnetic, catalytic, and other properties which provide suitability for specific technical and biomedical applications [9]. Surface of commercially available nanoparticles is normally modified by coating with different materials in order to stabilize them, modify their biodistribution, and enhance their biocompatibility. This coating is applied by adding a stabilizing coating material [e.g., citrate, dextran, carboxydextran, chitosan, pullulan, polyethylene glycol (PEG), polyvinyl alcohol (PVA), polyethylenimine (PEI), polyethylene oxide (PEO), polysaccharide, albumin, lipids, etc.] to monocrystalline (uniform ION with close particle size distribution) or polycrystalline (with significant size variance) ION [11]. Furthermore, particle coating may be further modified, especially in case of medical uses, with fluorescent dyes for imaging [12], [13], targeting molecules [13], [14], drugs [15] or nucleic acids [16], [17]. This great variety of coatings leads to many diverse types of ION with different potential action mechanisms and toxic patterns.
ION have been reported in many studies to be highly biocompatible nanomaterials with none or low toxicity which do not pose a serious threat to the organism [18], [19], [20], [21]. Despite being considered as generally safe, potential ION toxicity cannot be completely discarded since results from studies on this regard are often contradictory and ION effects at particular levels, such as genetic or carcinogenic, have been poorly addressed. Also, their effects on whole organisms and, specially, human health risks related to occupational and environmental exposure to ION have been scarcely evaluated. On this basis, and in order to improve the knowledge in this field, the aim of this review was to compile the in vitro, in vivo and epidemiological studies on ION toxicity published to date. Thus, the results and conclusions from the main ION toxicology studies were analysed, providing a general view of the current information on ION safety available as well as highlighting the main gaps of knowledge in the field that must be further addressed.
Section snippets
Cellular effects
Most studies analysing ION toxicity are focused on cytotoxic effects of these nanoparticles on cell cultures. A number of different cell lines and testing conditions have been assessed reporting ION cellular effects at different levels, mainly decrease in viability, ROS production, and iron ion release, but also apoptosis induction, cell cycle alterations, cell membrane disruptions, cytoskeleton modifications, etc. An exhaustive revision of the former works can be found in some previous papers
In vivo studies
Since nanomaterial studies based on cell cultures are often inconsistent and might underestimate their effects, toxicity of nanomaterials needs to be examined in whole animal systems [96]. Besides, nanomaterial uptake and distribution in the body are complex processes that cannot be properly addressed in cultured cells, and in vitro particle size can change when used in vivo due to the additional deposition of salts, opsonization with plasma proteins, lipids or carbohydrates, depending on the
Epidemiological studies
Epidemiological studies in the nanotoxicology field are very scarce. A limited number of nanomaterials, including titanium dioxide (TiO2) nanoparticles, carbon nanotubes (CNT) or incidental ultrafine nanoparticles, have been evaluated so far to determine the health risks associated with their occupational exposure [138]. Proper population studies on environmental nanomaterial exposure are even more limited, almost inexistent. This significant lack of studies is likely related to the difficulty
Concluding remarks
Due to their unique physicochemical properties, ION have a number of interesting current and potential future applications, especially in the biomedical field, that make them one of the most fascinating nanomaterials. Among other uses, they are currently employed in cell labelling, drug targeting, gene delivery, biosensors, hyperthermia therapy, and diagnostics, and they have promising future uses in therapies against cancer and other diseases. However, all these medical applications require
Conflict of interest
The authors did not report any conflict of interest.
Acknowledgements
This work was supported by Xunta de Galicia (EM 2012/079), the project NanoToxClass (ERA ERASIINN/001/2013), and by TD1204 MODENA COST Action.
References (141)
- et al.
Interactions with the human body
- et al.
Synthesis and surface engineering of iron oxide nanoparticles for biomedical applications
Biomaterials
(2005) - et al.
In vitro toxicity of nanoparticles in BRL 3A rat liver cells
Toxicol. In Vitro
(2005) - et al.
Efficient internalization of silica-coated iron oxide nanoparticles of different sizes by primary human macrophages and dendritic cells
Toxicol. Appl. Pharmacol.
(2011) - et al.
Nanotechnology, nanotoxicology, and neuroscience
Prog. Neurobiol.
(2009) - et al.
Ferritin up-regulation and transient ROS production in cultured brain astrocytes after loading with iron oxide nanoparticles
Acta Biomater.
(2012) - et al.
Polyacrylic acid coated and non-coated iron oxide nanoparticles are not genotoxic to human T lymphocytes
Toxicol. Lett.
(2015) - et al.
Accumulation of iron oxide nanoparticles by cultured primary neurons
Neurochem. Int.
(2015) - et al.
Neurotoxic potential of iron oxide nanoparticles in the rat brain striatum and hippocampus
Neurotoxicology
(2013) - et al.
Cell toxicity of superparamagnetic iron oxide nanoparticles
J. Colloid Interface Sci.
(2009)
Magnetic Fe3O4@mesoporous silica composites for drug delivery and bioadsorption
J. Colloid Interface Sci.
Size-dependent toxicity of metal oxide particles—a comparison between nano- and micrometer size
Toxicol. Lett.
Disturbance of ion environment and immune regulation following biodistribution of magnetic iron oxide nanoparticles injected intravenously
Toxicol. Lett.
Synthesis, characterization and toxicological evaluation of iron oxide nanoparticles in human lung alveolar epithelial cells
Colloids Surf. B Biointerfaces
Superparamagnetic iron oxide nanoparticles impair endothelial integrity and inhibit nitric oxide production
Acta Biomater.
In vitro evaluation of the cytotoxicity of iron oxide nanoparticles with different coatings and different sizes in A3 human T lymphocytes
Sci. Total Environ.
Cytotoxic effects of iron oxide nanoparticles and implications for safety in cell labelling
Biomaterials
Interaction of polyacrylic acid coated and non-coated iron oxide nanoparticles with human neutrophils
Toxicol. Lett.
Endothelial dysfunction and inflammation induced by iron oxide nanoparticle exposure: risk factors for early atherosclerosis
Toxicol. Lett.
Evaluating the cytotoxicity of palladium/magnetite nano-catalysts intended for wastewater treatment
Environ. Pollut.
Microglial activation, recruitment and phagocytosis as linked phenomena in ferric oxide nanoparticle exposure
Toxicol. Lett.
Treatment with iron oxide nanoparticles induces ferritin synthesis but not oxidative stress in oligodendroglial cells
Acta Biomater.
Ferritin as a source of iron for oxidative damage
Free Radic. Biol. Med.
Free radicals and antioxidants in normal physiological functions and human disease
Int. J. Biochem. Cell Biol.
The role of iron redox state in the genotoxicity of ultrafine superparamagnetic iron oxide nanoparticles
Biomaterials
The role of reactive oxygen species in the genotoxicity of surface-modified magnetite nanoparticles
Toxicol. Lett.
Comparative study of genotoxicity and tissue distribution of nano and micron sized iron oxide in rats after acute oral treatment
Toxicol. Appl. Pharmacol.
FDA report: ferumoxytol for intravenous iron therapy in adult patients with chronic kidney disease
Am. J. Hematol.
Synthesis, properties, and applications of iron nanoparticles
Small
Superparamagnetic iron oxide nanoparticles in biomedicine: applications and developments in diagnostics and therapy
Rofo
Bifunctional magnetic silica nanoparticles for highly efficient human stem cell labeling
Nano Lett.
Ferucarbotran (Resovist): a new clinically approved RES-specific contrast agent for contrast-enhanced MRI of the liver: properties, clinical development, and applications
Eur. Radiol.
The role of functionalized magnetic iron oxide nanoparticles in the central nervous system injury and repair: new potentials for neuroprotection with Cerebrolysin therapy
J. Nanosci. Nanotechnol.
Iron oxide nanoparticles suppress the production of IL-1beta via the secretory lysosomal pathway in murine microglial cells
Part. Fibre Toxicol.
Synthesis and applications of nano-structured iron oxides/hydroxides—a review
Int. J. Eng. Sci. Technol.
Recent advances in surface chemistry strategies for the fabrication of functional iron oxide based magnetic nanoparticles
Nanoscale
Fluorescence-modified superparamagnetic nanoparticles: intracellular uptake and use in cellular imaging
Langmuir
Transferrin-conjugated, fluorescein-loaded magnetic nanoparticles for targeted delivery across the blood-brain barrier
J. Mater. Sci. Mater. Med.
Targeted nanoparticle enhanced proapoptotic peptide as potential therapy for glioblastoma
Proc. Natl. Acad. Sci. U. S. A.
Targeting anticancer drugs to the brain. I: enhanced brain delivery of oxantrazole following administration in magnetic cationic microspheres
J. Drug Target.
Excretion and toxicity of gold-iron nanoparticles
Nanomedicine
Image-guided breast tumor therapy using a small interfering RNA nanodrug
Cancer Res.
Toxicity of metal oxide nanoparticles in mammalian cells
J. Environ. Sci. Health A Tox. Hazard. Subst. Environ. Eng.
Characterization quantification, and determination of the toxicity of iron oxide nanoparticles to the bone marrow cells
Int. J. Mol. Sci.
Assessing iron oxide nanoparticle toxicity in vitro: current status and future prospects
Nanomedicine (Lond.)
Fe3O4-PEI-RITC magnetic nanoparticles with imaging and gene transfer capability: development of a tool for neural cell transplantation therapies
Pharm. Res.
Uptake of dimercaptosuccinate-coated magnetic iron oxide nanoparticles by cultured brain astrocytes
Nanotechnology
Direct labeling of hMSC with SPIO: the long-term influence on toxicity, chondrogenic differentiation capacity, and intracellular distribution
Mol. Imaging Biol.
Longitudinal tracking of human fetal cells labeled with super paramagnetic iron oxide nanoparticles in the brain of mice with motor neuron disease
PLoS One
Multidentate catechol-based polyethylene glycol oligomers provide enhanced stability and biocompatibility to iron oxide nanoparticles
ACS Nano
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These authors contributed equally to this work.