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Magnetite Nanoparticle Safety

Superparamagnetic iron oxide nanoparticles are the only clinically approved metal oxide nanoparticles.1 Given that iron oxides magnetite (Fe3O4) and maghemite (γ-Fe2O3) occur naturally as nano-sized crystals in the Earth’s crust, it would seem that there is no intrinsic risk associated with these nanoparticles.

Magnetite nanoparticles have attracted much attention not only because of their superparamagnetic properties but also because they have been shown to have low toxicity in the human body. Currently, magnetite nanoparticles are used in a variety of biomedical applications, for example, magnetic resonance imaging, targeted delivery of drugs or genes, targeted destruction of tumor tissue through hyperthermia, magnetic transfections, iron detection, chelation therapy and tissue engineering.2

Uncoated magnetite nanoparticles have very low solubilities that can lead to precipitation and agglomeration under physiological conditions. To mediate these effects they are coated with materials such as silicon, dextran, citrate and PEGylated starch.3 The surface coating of iron oxide plays an important role in internalization effects.4

Several studies have examined the toxicity potential of several different types of magnetite nanoparticles with a range of surface coatings and have generally found low or no toxicity associated with these nanoparticles until high exposure levels (>100 mg/ml).5 The toxicity was also found to be dependent on various factors such as type of surface coating or its breakdown products, tail length, chemical composition of cell-medium, oxidation state and protein interaction.6

Exposure to magnetite particles also occurs in the environment. In one study, rat exposure to iron oxide dust was tolerated without mortality, consistent changes in body weights, food and water consumption or systemic toxicity.7 A study on subway particles (which are composed primarily of iron oxide) found these particulates to be toxic. However, magnetite particles on their own did not exhibit toxic effects, showing that the small percentage of other compounds in the dust was the cause of toxicity.8

Interestingly, not only have magnetite nanoparticles been found to be mostly nontoxic, they have also been shown to be beneficial for preventing protein aggregation.9 Based on this study, Fe3O4 nanoparticles could potentially be used as novel therapeutic agents in the treatment of protein aggregation-associated human pathologies.10

In conclusion, many studies have shown that magnetite nanoparticles with a range of surface coatings have low or no toxicity except at very high levels of exposure.

References

  1. Singha, N; Gareth, J.S.; Asadib, R.; Doak, S. H. “Potential toxicity of superparamagnetic iron oxide nanoparticles (SPION)” Nano Reviews 2010, 1, 5358
  2. A) Ito, A.; Shinkai, M.; Honda, H.; Kobayashi, T. “Medical application of functionalized magnetic nanoparticles” Biosci. Bioeng. 2005, 100, 1-11. B) Huber, D. L. “Synthesis, properties, and applications of iron nanoparticles” Small 2005, 1, 482-501. C) Gupta, A. K.; Gupta, M. “Synthesis and surface engineering of iron oxide nanoparticles for biomedical applications” Biomaterials 2005, 26, 3995-4021. D) Hautot, D.; Pankhurst, Q. A.; Morris, C. M.; Curtis, A.; Burn, J.; Dobson, J. “Preliminary observation of elevated levels of nanocrystalline iron oxide in the basal ganglia of neuroferritinopathy patients” Biochim. Biophys. Acta. 2007, 1772, 21-25. E) Liu, G.; Men, P.; Harris, P. L.; Rolston, R. K.; Perry, G.; Smith, M. A. “Nanoparticle iron chelators: a new therapeutic approach in Alzheimer disease and other neurologic disorders associated with trace metal imbalance” Neurosci. Lett. 2006, 406, 189-193. F) Bulte, J. W.; Douglas, T.; Witwer, B.; Zhang, S. C.; Strable, E.; Lewis, B. K. et al. “Magnetodendrimers allow endosomal magnetic labeling and in vivo tracking of stem cells” Nat. Biotechnol. 2001, 19, 1141-1147.
  3. A) Wang, Y. X.; Hussain, S. M.; Krestin, G. P. “Superparamagnetic iron oxide contrast agents: physicochemical characteristics and applications in MR imaging” Radiol. 2001, 11, 2319-2331. B) Sadeghiani, N.; Barbosa, L. S.; Silva, L. P.; Azevedo, R. B.; Morais, P. C.; Lacava, Z. G. M. “Genotoxicity and inflammatory investigation in mice treated with magnetite nanoparticles surface coated with polyaspartic acid” J. Magnetism Magnetic Materials 2005, 289, 466-468.
  4. A) Jain, T. K.; Reddy, M. K.; Morales, M. A.; Leslie-Pelecky, D. L.; Labhasetwar, V. “Biodistribution, clearance, and biocompatibility of iron oxide magnetic nanoparticles in rats” Pharm. 2008, 5, 316-327. B) Pisanic, T. R. 2nd; Blackwell, J. D; Shubayev, V. I.; Finones, R. R.; Jin, S. “Nanotoxicity of iron oxide nanoparticle internalization in growing neurons” Biomaterials 2007, 28, 2572-2581. C) Wilhelm, C.; Billotey, C.; Roger, J.; Pons, J. N.; Bacri, J. C.; Gazeau, F. “Intracellular uptake of anionic superparamagnetic nanoparticles as a function of their surface coating” Biomaterials 2003, 24, 1001-1011.
  5. A) Karlsson, H. L.; Cronholm, P.; Gustafsson, J.; Moller, L. “Copper oxide nanoparticles are highly toxic: a comparison between metal oxide nanoparticles and carbon nanotubes” Res. Toxicol. 2008, 21, 1726-1732. B) Ankamwar, B.; Lai, T. C.; Huang, J. H.; Liu, R. S.; Hsiao, M.; Chen, C. H.; et al. “Biocompatibility of Fe3O4 nanoparticles evaluated by in vitro cytotoxicity assays using normal, glia and breast cancer cells” Nanotechnology 2010, 21, 75102. C) Anzai, Y.; Piccoli, C. W.; Outwater, E. K.; Stanford, W.; Bluemke, D. A.; Nurenberg, P.; et al. “Evaluation of neck and body metastases to nodes with ferumoxtran 10-enhanced MR imaging: phase III safety and efficacy study” Radiology 2003, 228, 777-788. D) Auffan, M.; Decome, L.; Rose, J.; Orsiere, T.; De Meo, M.; Briois, V.; et al. “In vitro interactions between DMSA-coated maghemite nanoparticles and human fibroblasts: a physicochemical and cyto-genotoxical study” Environ. Sci. Technol. 2006, 40, 4367-4373.
  6. A) Mahmoudi, M.; Simchi, A.; Imani, M.; Shokrgozar, M. A.; Milani, A. S.; Hafeli, U. O.; et al. “A new approach for the in vitro identification of the cytotoxicity of superparamagnetic iron oxide nanoparticles” Colloids Surf. B. Biointerfaces. 2010, 75, 300-30 B) Mahmoudi, M.; Simchi, A.; Imani, M.; Milani, A. S.; Stroeve, P. “An in vitro study of bare and poly(ethylene glycol)-co-fumaratecoated superparamagnetic iron oxide nanoparticles: a new toxicity identification procedure” Nanotechnology 2009, 20, 225104. C) Berry, C. C.; Wells, S.; Charles, S.; Curtis, A. S. “Dextran and albumin derivatised iron oxide nanoparticles: influence on fibroblasts in vitro” Biomaterials 2003, 24, 4551-4557. D) Berry, C. C.; Wells, S.; Charles, S.; Aitchison, G.; Curtis, A. S. “Cell response to dextran-derivatised iron oxide nanoparticles post internalisation” Biomaterials 2004, 25, 5405-5413.
  7. Pauluhn, J. “Subchronic inhalation toxicity of iron oxide (magnetite, Fe3O4) in rats: pulmonary toxicity is determined by the particle kinetics typical of poorly soluble particles” Appl. Toxicol. 2012, 32, 488-504
  8. Karlsson, H. L.; Holgersson, A.; Moller, L. “Mechanisms related to the genotoxicity of particles in the subway and from other sources” Res. Toxicol. 2008, 21, 726-731.
  9. Bellova, A.; Bystrenova, E.; Koneracka, M.; Kopcansky, P.; Valle, F.; Tomasovicova, N.; et al. “Effect of Fe3O4 magnetic nanoparticleson lysozyme amyloid aggregation” Nanotechnology 2010, 21, 065103.
  10. Vieira, M. N.; Figueroa-Villar, J. D.; Meirelles, M. N.; Ferreira, S. T.; De Felice, F. G. “Small molecule inhibitors of lysozyme amyloid aggregation” Cell Biochem. Biophys. 2006, 44, 549-5