Nano Research

, Volume 9, Issue 8, pp 2398–2410 | Cite as

Ferritin surplus in mouse spleen 14 months after intravenous injection of iron oxide nanoparticles at clinical dose

  • Alexandre TamionEmail author
  • Matthias HillenkampEmail author
  • Arnaud Hillion
  • Valentin A. Maraloiu
  • Ioana D. Vlaicu
  • Mariana Stefan
  • Daniela Ghica
  • Hugo Rositi
  • Fabien Chauveau
  • Marie-Geneviève Blanchin
  • Marlène Wiart
  • Véronique Dupuis
Research Article


In this study, we followed the biodegradation of ultra-small superparamagnetic iron oxide nanoparticles injected intravenously at clinical doses in mice. An advanced fitting procedure for magnetic susceptibility curves and low-temperature hysteresis loops was used to fully characterize the magnetic size distribution as well as the magnetic anisotropy energy of the injected P904 nanoparticles (Guerbet Laboratory). Additional magnetometry measurements and transmission electronic microscopy observations were systematically performed to examine dehydrated samples from the spleen and liver of healthy C57B16 mice after nanoparticle injection, with sacrifice of the mice for up to 14 months. At 3 months after injection, the magnetic properties of the spleen and liver were dramatically different. While the liver showed no magnetic signals other than those also present in the reference species, the spleen showed an increased magnetic signal attributed to ferritin. This surplus of ferritin remained constant up to 14 months after injection.


nanoparticles biodegradation iron oxide nanomagnetism contrast agent 


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  1. [1]
    Yen, S. K.; Padmanabhan, P.; Selvan, S. T. Multifunctional iron oxide nanoparticles for diagnostics, therapy and macromolecule delivery. Theranostics 2013, 3, 986–1003.CrossRefGoogle Scholar
  2. [2]
    Wu, L. C.; Cao, Y. F.; Liao, C.; Huang, J. H.; Gao, F. Diagnostic performance of USPIO-enhanced MRI for lymphnode metastases in different body regions: A meta-analysis. Eur. J. Radiol. 2011, 80, 582–589.CrossRefGoogle Scholar
  3. [3]
    Harnan, S. E.; Cooper, K. L.; Meng, Y.; Ward, S. E.; Fitzgerald, P.; Papaioannou, D.; Ingram, C.; Lorenz, E.; Wilkinson, I. D.; Wyld, L. Magnetic resonance for assessment of axillary lymph node status in early breast cancer: A systematic review and meta-analysis. Eur. J. Surg. Oncol. 2011, 37, 928–936.CrossRefGoogle Scholar
  4. [4]
    Aime, S.; Caravan, P. Biodistribution of gadolinium-based contrast agents, including gadolinium deposition. J. Magn. Reson. Imaging 2009, 30, 1259–1267.CrossRefGoogle Scholar
  5. [5]
    Corot, C.; Robert, P.; Idée, J.-M.; Port, M. Recent advances in iron oxide nanocrystal technology for medical imaging. Adv. Drug Deliv. Rev. 2006, 58, 1471–1504.CrossRefGoogle Scholar
  6. [6]
    López-Castro, J. D.; Maraloiu, A. V.; Delgado, J. J.; Calvino, J. J.; Blanchin, M.-G.; Gálvez, N.; Dominguez-Vera, J. M. From synthetic to natural nanoparticles: Monitoring the biodegradation of SPIO (P904) into ferritin by electron microscopy. Nanoscale 2011, 3, 4597–4599.CrossRefGoogle Scholar
  7. [7]
    Lévy, M.; Lagarde, F.; Maraloiu, V.-A.; Blanchin, M.-G.; Gendron, F.; Wilhelm, C.; Gazeau, F. Degradability of superparamagnetic nanoparticles in a model of intracellular environment: Follow-up of magnetic, structural and chemical properties. Nanotechnology 2010, 21, 395103.CrossRefGoogle Scholar
  8. [8]
    Levy, M.; Luciani, N.; Alloyeau, D.; Elgrabli, D.; Deveaux, V.; Pechoux, C.; Chat, S.; Wang, G.; Vats, N.; Gendron, F. et al. Long term in vivo biotransformation of iron oxide nanoparticles. Biomaterials 2011, 32, 3988–3999.CrossRefGoogle Scholar
  9. [9]
    Levy, M.; Wilhelm, C.; Luciani, N.; Deveaux, V.; Gendron, F.; Luciani, A.; Devaud, M.; Gazeau, F. Nanomagnetism reveals the intracellular clustering of iron oxide nanoparticles in the organism. Nanoscale 2011, 3, 4402–4410.CrossRefGoogle Scholar
  10. [10]
    Lévy, M.; Wilhelm, C.; Devaud, M.; Levitz, P.; Gazeau, F. How cellular processing of superparamagnetic nanoparticles affects their magnetic behavior and NMR relaxivity. Contrast Media Mol. Imaging 2012, 7, 373–383.CrossRefGoogle Scholar
  11. [11]
    Lartigue, L.; Alloyeau, D.; Kolosnjaj-Tabi, J.; Javed, Y.; Guardia, P.; Riedinger, A.; Péchoux, C.; Pellegrino, T.; Wilhelm, C.; Gazeau, F. Biodegradation of iron oxide nanocubes: High-resolution in situ monitoring. ACS Nano 2013, 7, 3939–3952.CrossRefGoogle Scholar
  12. [12]
    Pauling, L.; Coryell, C. D. The magnetic properties and structure of hemoglobin, oxyhemoglobin and carbonmonoxyhemoglobin. Proc. Natl. Acad. Sci. USA 1936, 22, 210–216.CrossRefGoogle Scholar
  13. [13]
    Bell, S. H.; Weir, M. P.; Dickson, D. P.; Gibson, J. F.; Sharp, G. A.; Peters, T. J. Mössbauer spectroscopic studies of human haemosiderin and ferritin. Biochim. Biophys. Acta 1984, 787, 227–236.CrossRefGoogle Scholar
  14. [14]
    Tamion, A.; Hillenkamp, M.; Tournus, F.; Bonet, E.; Dupuis, V. Accurate determination of the magnetic anisotropy in cluster-assembled nanostructures. Appl. Phys. Lett. 2009, 95, 062503.CrossRefGoogle Scholar
  15. [15]
    Tamion, A.; Bonet, E.; Tournus, F.; Raufast, C.; Hillion, A.; Gaier, O.; Dupuis, V. Efficient hysteresis loop simulations of nanoparticle assemblies beyond the uniaxial anisotropy. Phys. Rev. B 2012, 85, 134430.CrossRefGoogle Scholar
  16. [16]
    Sigovan, M.; Boussel, L.; Sulaiman, A.; Sappey-Marinier, D.; Alsaid, H.; Desbleds-Mansard, C.; Ibarrola, D.; Gamondès, D.; Corot, C.; Lancelot, E. et al. Rapid-clearance iron nanoparticles for inflammation imaging of atherosclerotic plaque: Initial experience in animal model. Radiology 2009, 252, 401–409.CrossRefGoogle Scholar
  17. [17]
    Wilhelm, C.; Gazeau, F.; Bacri, J.-C. Magnetophoresis and ferromagnetic resonance of magnetically labeled cells. Eur. Biophys. J. 2002, 31, 118–125.CrossRefGoogle Scholar
  18. [18]
    Jamet, M.; Wernsdorfer, W.; Thirion, C.; Mailly, D.; Dupuis, V.; Mélinon, P.; Pérez, A. Magnetic anisotropy of a single cobalt nanocluster. Phys. Rev. Lett. 2001, 86, 4676–4679.CrossRefGoogle Scholar
  19. [19]
    Oyarzún, S.; Tamion, A.; Tournus, F.; Dupuis, V.; Hillenkamp, M. Size effects in the magnetic anisotropy of embedded cobalt nanoparticles: From shape to surface. Sci. Rep. 2015, 5, 14749.CrossRefGoogle Scholar
  20. [20]
    Thiaville, A. Coherent rotation of magnetization in three dimensions: A geometrical approach. Phys. Rev. B 2000, 61, 12221–12232.CrossRefGoogle Scholar
  21. [21]
    Gutiérrez, L.; Lázaro, F. J.; Abadía, A. R.; Romero, M. S.; Quintana, C.; Morales, M. P.; Patiño, C.; Arranz, R. Bioinorganic transformations of liver iron deposits observed by tissue magnetic characterisation in a rat model. J. Inorg. Biochem. 2006, 100, 1790–1799.CrossRefGoogle Scholar
  22. [22]
    Lévy, M.; Gazeau, F.; Bacri, J.-C.; Wilhelm, C.; Devaud, M. Modeling magnetic nanoparticle dipole–dipole interactions inside living cells. Phys. Rev. B 2011, 84, 075480.CrossRefGoogle Scholar
  23. [23]
    Henkel, O. Remanenzverhalten und Wechselwirkungen in hartmagnetischen Teilchenkollektiven. Phys. Stat. Sol. B 1964, 7, 919–929.CrossRefGoogle Scholar
  24. [24]
    Gamarra, L. F.; Pontuschka, W. M.; Amaro, E., Jr.; Costa-Filho, A. J.; Brito, G. E. S.; Vieira, E. D.; Carneiro, S. M.; Escriba, D. M.; Falleiros, A. M. F.; Salvador, V. L. Kinetics of elimination and distribution in blood and liver of biocompatible ferrofluids based on Fe3O4 nanoparticles: An EPR and XRF study. Mater. Sci. Eng. C 2008, 28, 519–525.CrossRefGoogle Scholar
  25. [25]
    Luciani, N.; Wilhelm, C.; Gazeau, F. The role of cell-released microvesicles in the intercellular transfer of magnetic nanoparticles in the monocyte/macrophage system. Biomaterials 2010, 31, 7061–7069.CrossRefGoogle Scholar
  26. [26]
    Allen, P. D.; St Pierre, T. G.; Chua-anusorn, W.; Ström, V.; Rao, K. V. Low-frequency low-field magnetic susceptibility of ferritin and hemosiderin. Biochim. Biophys. Acta 2000, 1500, 186–196.CrossRefGoogle Scholar
  27. [27]
    Brem, F.; Stamm, G.; Hirt, A. M. Modeling the magnetic behavior of horse spleen ferritin with a two-phase core structure. J. Appl. Phys. 2006, 99, 123906.CrossRefGoogle Scholar
  28. [28]
    Mohie-Eldin, M.-E.; Frankel, R. B.; Gunther, L. A comparison of the magnetic properties of polysaccharide iron complex (PIC) and ferritin. J. Magn. Magn. Mater. 1994, 135, 65–81.CrossRefGoogle Scholar
  29. [29]
    Tejada, J.; Zhang, X. X. On magnetic relaxation in antiferromagnetic horse-spleen ferritin proteins. J. Phys.: Condens. Matter 1994, 6, 263–266.Google Scholar
  30. [30]
    Kilcoyne, S. H.; Cywinski, R. Ferritin: A model superparamagnet. J. Magn. Magn. Mater. 1995, 140–144, 1466–1467.CrossRefGoogle Scholar
  31. [31]
    Makhlouf, S. A.; Parker, F. T.; Berkowitz, A. E. Magnetic hysteresis anomalies in ferritin. Phys. Rev. B 1997, 55, R14717–R14720.CrossRefGoogle Scholar
  32. [32]
    Maraloiu, V. A.; Blanchin, M.-G. Multiscale Study of Magnetic Nanovectors; Scholars’ Press: Saarbrücken, Germany, 2013.Google Scholar
  33. [33]
    Wood, J. C. Guidelines for quantifying iron overload. In Hematology/the Education Program of the American Society of Hematology American Society of Hematology Education Program; The Society: Washington, DC, 2014; pp 210–215.Google Scholar
  34. [34]
    Storey, P.; Lim, R. P.; Chandarana, H.; Rosenkrantz, A. B.; Kim, D.; Stoffel, D. R.; Lee, V. S. MRI assessment of hepatic iron clearance rates after USPIO administration in healthy adults. Invest. Radiol. 2012, 47, 717–724.CrossRefGoogle Scholar
  35. [35]
    Hunter, J. E. Variable effects of iron status on the concentration of ferritin in rat plasma, liver, and spleen. J. Nutr. 1978, 108, 497–505.Google Scholar
  36. [36]
    Richter, G. W. The iron-loaded cell—The cytopathology of iron storage. A review. Am. J. Pathol. 1978, 91, 362–404.Google Scholar
  37. [37]
    Gustafson, H. H.; Holt-Casper, D.; Grainger, D. W.; Ghandehari, H. Nanoparticle uptake: The phagocyte problem. Nano Today 2015, 10, 487–510.CrossRefGoogle Scholar

Copyright information

© Tsinghua University Press and Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Alexandre Tamion
    • 1
    Email author
  • Matthias Hillenkamp
    • 1
    Email author
  • Arnaud Hillion
    • 1
    • 5
  • Valentin A. Maraloiu
    • 2
  • Ioana D. Vlaicu
    • 2
  • Mariana Stefan
    • 2
  • Daniela Ghica
    • 2
  • Hugo Rositi
    • 3
  • Fabien Chauveau
    • 4
  • Marie-Geneviève Blanchin
    • 1
  • Marlène Wiart
    • 3
  • Véronique Dupuis
    • 1
  1. 1.Institut Lumière Matière, UMR5306 Université Lyon 1- CNRSUniversité de LyonVilleurbanne cedexFrance
  2. 2.National Institute of Materials PhysicsBucharest-MagureleRomania
  3. 3.CNRS, UMR 5220, INSERM, U1044, INSA de LyonUniversité de Lyon, Lyon 1, CREATISLyonFrance
  4. 4.CRNL-BIORAN, CNRS UMR5292, INSERM U1028Université Lyon 1BronFrance
  5. 5.Institut Jean LamourUMR 7198 – Université de Lorraine, Parc de SauruptNancyFrance

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