Journal of Nanoparticle Research

, Volume 12, Issue 1, pp 151–160 | Cite as

Immunological impact of magnetic nanoparticles (Ferucarbotran) on murine peritoneal macrophages

  • Chen-Hao Yeh
  • Jong-Kai Hsiao
  • Jaw-Lin Wang
  • Fuu Sheu
Research Paper


Ferucarbotran, a clinically used superparamagnetic iron oxide, is widely developed as a magnetic resonance imaging (MRI) contrast agent and has the potential to improve the monitoring of macrophage recirculation in vivo. However, the biological effect of Ferucarbotran or magnetic nanoparticles (MNPs) on macrophage is not clearly understood yet. This study is aimed to examine the immunological impact of Ferucarbotran toward murine peritoneal macrophages. Cells treated with Ferucarbotran demonstrated a dose–responsive increase of granularity in the cytoplasm. After 24 h of incubation, viability and cytotoxicity in macrophages treated with 200 μg Fe/mL of Ferucarbotran were not affected. Macrophages loaded with Ferucarbotran above 100 μg Fe/mL showed a significant (p < 0.01) increase in cytokine (TNF-α, IL-1β, IL-6) secretion and mRNA expression, followed by nitric oxide (NO) secretion and iNOS mRNA expression. Chemotactic responses of Ferucarbotran-preloaded macrophages toward CX3CL1 were significantly (p < 0.05) lower than those of untreated macrophages. Taking together, Ferucarbotran at high dose (100 μg Fe/mL) could induce murine peritoneal macrophages activation in pro-inflammatory cytokine secretion and NO production.


Superparamagnetic iron oxide Magnetic resonance imaging Cytotoxicity Inflammation Cell activation Chemotaxis Nanomedicine 



Magnetic nanoparticles


Magnetic resonance imaging


Superparamagnetic iron oxide


Ultrasmall superparamagnetic iron oxide



This study was supported by grants from the National Science Council, Taiwan (NSC-96-2815-C-002-080-B).

Supplementary material

11051_2009_9589_MOESM1_ESM.doc (46 kb)
Supplementary material 1 (DOC 46 kb)


  1. Arbab AS, Bashaw LA, Miller BR et al (2003) Characterization of biophysical and metabolic properties of cells labeled with superparamagnetic iron oxide nanoparticles and transfection agent for cellular MR imaging. Radiology 229:838–846. doi: 10.1148/radiol.2293021215 CrossRefPubMedGoogle Scholar
  2. Arbab AS, Yocum GT, Kalish H et al (2004) Efficient magnetic cell labeling with protamine sulfate complexed to ferumoxides for cellular MRI. Blood 104:1217–1223. doi: 10.1182/blood-2004-02-0655 CrossRefPubMedGoogle Scholar
  3. Arbab AS, Yocum GT, Rad AM et al (2005) Labeling of cells with ferumoxides-protamine sulfate complexes does not inhibit function or differentiation capacity of hematopoietic or mesenchymal stem cells. NMR Biomed 18:553–559. doi: 10.1002/nbm.991 CrossRefPubMedGoogle Scholar
  4. Barlic J, Sechler JM, Murphy PM (2003) IL-15 and IL-2 oppositely regulate expression of the chemokine receptor CX3CR1. Blood 102:3494–3503. doi: 10.1182/blood-2003-03-0946 CrossRefPubMedGoogle Scholar
  5. Bazan JF, Bacon KB, Hardiman G et al (1997) A new class of membrane-bound chemokine with a CX3C motif. Nature 385:640–644. doi: 10.1038/385640a0 CrossRefPubMedADSGoogle Scholar
  6. Chen JJ, Lin YC, Yao PL et al (2005) Tumor-associated macrophages: the double-edged sword in cancer progression. J Clin Oncol 23:953–964. doi: 10.1200/JCO.2005.12.172 CrossRefPubMedGoogle Scholar
  7. Corot C, Petry KG, Trivedi R et al (2004) Macrophage imaging in central nervous system and in carotid atherosclerotic plaque using ultrasmall superparamagnetic iron oxide in magnetic resonance imaging. Invest Radiol 39:619–625. doi: 10.1097/01.rli.0000135980.08491.33 CrossRefPubMedGoogle Scholar
  8. Corot C, Robert P, Idee JM, Port M (2006) Recent advances in iron oxide nanocrystal technology for medical imaging. Adv Drug Deliv Rev 58:1471–1504. doi: 10.1016/j.addr.2006.09.013 CrossRefPubMedGoogle Scholar
  9. Daldrup-Link HE, Rudelius M, Oostendorp RA et al (2003) Targeting of hematopoietic progenitor cells with MR contrast agents. Radiology 228:760–767. doi: 10.1148/radiol.2283020322 CrossRefPubMedGoogle Scholar
  10. Dodd SJ, Williams M, Suhan JP, Williams DS, Koretsky AP, Ho C (1999) Detection of single mammalian cells by high-resolution magnetic resonance imaging. Biophys J 76:103–109CrossRefPubMedGoogle Scholar
  11. Dousset V, Delalande C, Ballarino L et al (1999) In vivo macrophage activity imaging in the central nervous system detected by magnetic resonance. Magn Reson Med 41:329–333. doi:10.1002/(SICI)1522-2594(199902)41:2<329::AID-MRM17>3.0.CO;2-ZCrossRefPubMedGoogle Scholar
  12. Floris S, Blezer EL, Schreibelt G et al (2004) Blood–brain barrier permeability and monocyte infiltration in experimental allergic encephalomyelitis: a quantitative MRI study. Brain 127:616–627. doi: 10.1093/brain/awh068 CrossRefPubMedGoogle Scholar
  13. Fotakis G, Timbrell JA (2006) In vitro cytotoxicity assays: comparison of LDH, neutral red, MTT and protein assay in hepatoma cell lines following exposure to cadmium chloride. Toxicol Lett 160:171–177. doi: 10.1016/j.toxlet.2005.07.001 CrossRefPubMedGoogle Scholar
  14. Gevrey JC, Isaac BM, Cox D (2005) Syk is required for monocyte/macrophage chemotaxis to CX3CL1 (Fractalkine). J Immunol 175:3737–3745PubMedGoogle Scholar
  15. Green LC, Wagner DA, Glogowski J, Skipper PL, Wishnok JS, Tannenbaum SR (1982) Analysis of nitrate, nitrite, and [15N]nitrate in biological fluids. Anal Biochem 126:131–138. doi: 10.1016/0003-2697(82)90118-X CrossRefPubMedGoogle Scholar
  16. Hamm B, Staks T, Taupitz M (1994a) SHU 555A A new superparamagnetic iron oxide contrast agent for magnetic resonance imaging. Invest Radiol 29(Suppl 2):S87–S89. doi: 10.1097/00004424-199406001-00029 PubMedCrossRefGoogle Scholar
  17. Hamm B, Staks T, Taupitz M et al (1994b) Contrast-enhanced MR imaging of liver and spleen: first experience in humans with a new superparamagnetic iron oxide. J Magn Reson Imaging 4:659–668. doi: 10.1002/jmri.1880040508 CrossRefPubMedGoogle Scholar
  18. Hinds KA, Hill JM, Shapiro EM et al (2003) Highly efficient endosomal labeling of progenitor and stem cells with large magnetic particles allows magnetic resonance imaging of single cells. Blood 102:867–872. doi: 10.1182/blood-2002-12-3669 CrossRefPubMedGoogle Scholar
  19. Hsiao JK, Chu HH, Wang YH et al (2008) Macrophage physiological function after superparamagnetic iron oxide labeling. NMR Biomed 21:820–829. doi: 10.1002/nbm.1260 CrossRefPubMedGoogle Scholar
  20. Jendelova P, Herynek V, De Croos J et al (2003) Imaging the fate of implanted bone marrow stromal cells labeled with superparamagnetic nanoparticles. Magn Reson Med 50:767–776. doi: 10.1002/mrm.10585 CrossRefPubMedGoogle Scholar
  21. Kimball ES, Kovacs E, Clark MC, Schneider CR (1995) Activation of cytokine production and adhesion molecule expression on THP-1 myelomonocytic cells by macrophage colony-stimulating factor in combination with interferon-gamma. J Leukoc Biol 58:585–594PubMedGoogle Scholar
  22. Krieg FM, Andres RY, Winterhalter KH (1995) Superparamagnetically labelled neutrophils as potential abscess-specific contrast agent for MRI. Magn Reson Imaging 13:393–400. doi: 10.1016/0730-725X(94)00111-F CrossRefPubMedGoogle Scholar
  23. Metz S, Bonaterra G, Rudelius M, Settles M, Rummeny EJ, Daldrup-Link HE (2004) Capacity of human monocytes to phagocytose approved iron oxide MR contrast agents in vitro. Eur Radiol 14:1851–1858. doi: 10.1007/s00330-004-2405-2 CrossRefPubMedGoogle Scholar
  24. Moghimi SM, Hunter AC, Murray JC (2005) Nanomedicine: current status and future prospects. FASEB J 19:311–330. doi: 10.1096/fj.04-2747rev CrossRefPubMedGoogle Scholar
  25. Mosmann T (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 65:55–63. doi: 10.1016/0022-1759(83)90303-4 CrossRefPubMedGoogle Scholar
  26. Muller K, Skepper JN, Posfai M et al (2007) Effect of ultrasmall superparamagnetic iron oxide nanoparticles (Ferumoxtran-10) on human monocyte-macrophages in vitro. Biomaterials 28:1629–1642. doi: 10.1016/j.biomaterials.2006.12.003 CrossRefPubMedGoogle Scholar
  27. Muller K, Skepper JN, Tang TY et al (2008) Atorvastatin and uptake of ultrasmall superparamagnetic iron oxide nanoparticles (Ferumoxtran-10) in human monocyte-macrophages: implications for magnetic resonance imaging. Biomaterials 29:2656–2662. doi: 10.1016/j.biomaterials.2008.03.006 CrossRefPubMedGoogle Scholar
  28. Oca-Cossio J, Mao H, Khokhlova N et al (2004) Magnetically labeled insulin-secreting cells. Biochem Biophys Res Commun 319:569–575. doi: 10.1016/j.bbrc.2004.04.195 CrossRefPubMedGoogle Scholar
  29. Pan Y, Lloyd C, Zhou H et al (1997) Neurotactin, a membrane-anchored chemokine upregulated in brain inflammation. Nature 387:611–617. doi: 10.1038/42491 CrossRefPubMedADSGoogle Scholar
  30. Pawelczyk E, Arbab AS, Pandit S, Hu E, Frank JA (2006) Expression of transferrin receptor and ferritin following ferumoxides-protamine sulfate labeling of cells: implications for cellular magnetic resonance imaging. NMR Biomed 19:581–592. doi: 10.1002/nbm.1038 CrossRefPubMedGoogle Scholar
  31. Rausch M, Hiestand P, Baumann D, Cannet C, Rudin M (2003) MRI-based monitoring of inflammation and tissue damage in acute and chronic relapsing EAE. Magn Reson Med 50:309–314. doi: 10.1002/mrm.10541 CrossRefPubMedGoogle Scholar
  32. Raynal I, Prigent P, Peyramaure S, Najid A, Rebuzzi C, Corot C (2004) Macrophage endocytosis of superparamagnetic iron oxide nanoparticles: mechanisms and comparison of ferumoxides and ferumoxtran-10. Invest Radiol 39:56–63. doi: 10.1097/01.rli.0000101027.57021.28 CrossRefPubMedGoogle Scholar
  33. Reimer P, Balzer T (2003) Ferucarbotran (Resovist): a new clinically approved RES-specific contrast agent for contrast-enhanced MRI of the liver: properties, clinical development, and applications. Eur Radiol 13:1266–1276PubMedGoogle Scholar
  34. Smirnov P, Lavergne E, Gazeau F et al (2006) In vivo cellular imaging of lymphocyte trafficking by MRI: a tumor model approach to cell-based anticancer therapy. Magn Reson Med 56:498–508. doi: 10.1002/mrm.20996 CrossRefPubMedGoogle Scholar
  35. Zhang Y, Dodd SJ, Hendrich KS, Williams M, Ho C (2000) Magnetic resonance imaging detection of rat renal transplant rejection by monitoring macrophage infiltration. Kidney Int 58:1300–1310. doi: 10.1046/j.1523-1755.2000.00286.x CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2009

Authors and Affiliations

  • Chen-Hao Yeh
    • 1
  • Jong-Kai Hsiao
    • 2
  • Jaw-Lin Wang
    • 3
  • Fuu Sheu
    • 1
    • 4
  1. 1.Department of HorticultureNational Taiwan UniversityTaipeiTaiwan, ROC
  2. 2.Department of Medical ImagingNational Taiwan University Hospital and College of MedicineTaipeiTaiwan, ROC
  3. 3.Institute of Biomedical EngineeringNational Taiwan UniversityTaipeiTaiwan, ROC
  4. 4.Research Center of Food and BiomoleculesNational Taiwan UniversityTaipeiTaiwan, ROC

Personalised recommendations