ToxicologySub-acute intravenous exposure to Fe2O3 nanoparticles does not alter cognitive performances and catecholamine levels, but slightly disrupts plasma iron level and brain iron content in rats
Introduction
Nanotechnology represents a complex domain that involves different fields such as electrical engineering, physics, chemistry, biology and medicine. The latter field, called nanomedicine [1], provides new tools of diagnosis and therapy based on nanomaterials. Among them, Iron oxide Nanoparticles (Fe2O3-NPs) are widely used in nanomedicine and also in other fields such as biology and environment [2]. In vivo, applications of Fe2O3-NPs could be classified as therapeutic, delivery and diagnostic (Magnetic Resonance Imaging (MRI)) agents; whereas for in vitro applications, the main use is in diagnosis (separation/selection and magnetic relaxometry) [3]. Indeed, the blood-brain barrier presents a real obstacle for the drug delivery to the brain, particularly for the treatment of neurodegenerative diseases, notably Alzheimer and Parkinson Diseases as well as brain cancers. Thus, the encapsulation of drugs in the NPs or their coupling to NPs could overcome the obstacle of the blood-brain barrier [4]. They can penetrate into the brain via transport along the nerves or through the blood brain barrier [5].The surface of these NPs can be modified by coating, which modifies their physicochemical properties and opens their use in nanomedicine [6,7]. Kim et al. [8] reported that among several engineered coated Fe2O3-NPs, dimercaptosuccinic acid coated Fe2O3 (DMSA-Fe2O3NPs) were potent pro-apoptotic agents for the rat sciatic nerve, and have also differential ability to regulate oxidative stress, inflammation and apoptotic signaling in several other cells notably in neuroglia, macrophages, lymphocytes and endothelial cells. Recently, Sun et al. [9], showed, using a model of derived cell line from the mouse brain, that the application of a magnetic field, stimulating convection and diffusion of Fe2O3-NPs, increases the permeability of these NPs through the blood-brain barrier. This change is in favor of a possible use of Fe2O3-NPs in the delivery of drugs to the central nervous system. Furthermore, another team reported that the intravenous delivery of biocompatible magnetic Fe2O3-NPs is able to load specifically the tumor in mice with subcutaneous squamous cell carcinoma [10]. With well determined thermal induction and a tumor to non-tumor ratio higher than 16, precise tumor ablation becomes possible. Thus, this finding can be used clinically in combination with chemotherapy or radiotherapy to enhance their efficacy. Besides their anti-tumor applications, Fe2O3-NPs based drugs such as ferumoxide and ferucarbotran are used in MRI as contrast agents, due to their biocompatibility, biodegradability and strong contrast enhancement [6,11]. Ferumoxytol (Feraheme®) is also used for the treatment of iron deficiency anemia in adults suffering from chronic kidney disease. This treatment was approved in 2009 by the Food and Drug Administration (FDA) and in 2012 by the European Medicines Agency (EMA) as a treatment to be administered intravenously [12]. However, in March 2015, the FDA warned about risks of anaphylactic shock in people who have an allergy to any intravenous iron substitute [13]. Thus, Fe2O3-NPs biological properties should be carefully studied to better understand the effects of these Fe2O3-NPs in the body [14]. The toxicological properties, namely nanotoxicology, depend on the characteristics of the nanoparticulate size and the chemical composition of the particle.
Several in vitro and in vivo studies have been conducted in this context, using various cell models and different routes of exposure in animals [8,[14], [15], [16], [17], [18], [19], [20]]. Nevertheless, the effects of Fe2O3-NPs on brain (behavior and neurotransmitters levels) are not well understood and studies are necessary to better clarify those effects, to minimize the risks and to increase the benefits for the use of the Fe2O3-NPs in nanomedicine. In this study, we investigated the possible toxic effects of sub-acute intravenous administration of Fe2O3-NPs in rats. Thereby, the effects of those nanoparticles on cognitive performances and the content of neurotransmitters and iron in brain were analyzed. The hematological and biochemical parameters as well as the organ histopathological modification were also examined.
Section snippets
Synthesis and characterization of iron oxide nanoparticles Fe2O3-NPs
Fe2O3-NPs used in this paper were gently provided by the Laboratory of Physics of Materials and Nanomaterials applied to the Environment at the Faculty of Sciences of Gabes under the direction of Professor Lassaad El Mir. Samples of Fe2O3-NPs were prepared by a modified sol-gel method under supercritical conditions of ethyl alcohol (EtOH). The particle size was adjusted by magnetic stirring time of 48 h, producing NPs with an average diameter of 30 nm [21]. Fe2O3-NPs were characterized by X-ray
Fe2O3-NPs characterization
Using TEM, Fe2O3-NPs show a spherical shape and an average size about 30 nm. Moreover, Energy dispersive X-ray (EDX) spectra of Fe2O3-NPs showed that there are no other elemental impurities present in theseFe2O3-NPs. In solution, the size of particles and their agglomerates were estimated by DLS, using Malvern Zetasizer Nano ZS and DTS Nano Software. This technique measures the Brownian motion of particles and relates it to the particle size. The mean hydrodynamic size was around 175 nm (Table 1
Discussion
With the increasing production and use of Fe2O3-NPs, human body may be voluntarily or involuntarily exposed to these nanoparticles via various possible routes among them the intravenous penetration [29]. Thus, Fe2O3-NPs may be distributed through the systemic circulation in several tissues including the brain. Interestingly, the intravenous pathway is considered as the most important route of administration to the body for the use of Iron Oxide Nanoparticles in Medicine. Young adult Wistar rats
Conclusion
To conclude, the increasing production of NPs and their parallel increasing use in the industry, as well as their presence in food, cosmetics and drugs, represent a research topic that is always growing and necessitate a better evaluation of the risks to improve the safety of these NPs. In the conditions of our experiment, i.e. sub-acute intravenous administration of 10 mg/kg Fe2O3-NPs for 7 days followed by 7 days of washout appeared safe for Wistar rats as evidenced by the stability of blood
Declaration of interests
The authors report no conflicts of interest in this work.
Funding
This study was supported by the Tunisian Ministry of Higher Education and Scientific Research and the Auvergne Rhone-Alpes Region (grant N° 16.007278.01 for Dalel Askri). Sylvia G. Lehmann received funding from Excellence Initiative of Aix-Marseille University – A*MIDEX, a French “Investissements d’Avenir” program, through its associated Labex SERENADE project”.
Acknowledgments
We would like to thank Professor Lassaad El Mir for providing Iron Oxide Nanoparticles, Mr Abdessalem Kouki for the access to the Transmission Electron Microscope and the equipex NanoID (ANR-10-EQPX-39) for the access to the nanoZS. Thanks also to Professor Nathalie Sturm and her team for their help in the histopathological examination.
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