title: The in-vivo use of superparamagnetic iron oxide nanoparticles to detect inflammation elicits a cytokine response but does not aggravate experimental arthritis.
abstract: BACKGROUND
  Superparamagnetic Iron Oxide Nanoparticles (SPION) are used in diagnostic imaging of a variety of different diseases. For such in-vivo application, an additional coating with a polymer, for example polyvinyl alcohol (PVA), is needed to stabilize the SPION and prevent aggregation. As the particles are foreign to the body, reaction against the SPION could occur. In this study we investigated the effects that SPION may have on experimental arthritis after intra-articular (i.a.) or intravenous (i.v.) injection.
  
  
  METHODS
  PVA-coated SPION were injected either i.a. (6 or 24 μg iron) or i.v. (100 μg or 1 mg iron) into naïve Toll-like receptor-4 deficient (TLR4-/-) or wild-type C57Bl/6 mice, or C57Bl/6 mice with antigen-induced arthritis. As control, some mice were injected with PVA or PBS. MR imaging was performed at 1 and 7 days after injection. Mice were sacrificed 2 hours and 1, 2, 7, 10 and 14 days after injection of the SPION, and RNA from synovium and liver was isolated for pro-inflammatory gene expression analysis. Serum cytokine measurements and whole knee joint histology were also performed.
  
  
  RESULTS
  Injection of a high dose of SPION or PVA into naïve knee joints resulted in an immediate upregulation of pro-inflammatory gene expression in the synovium. A similar gene expression profile was observed after SPION or PVA injection into knee joints of TLR4-/- mice, indicating that this effect is not due to LPS contamination. Histological analysis of the knee joints also revealed synovial inflammation after SPION injection. Two hours after i.v. injection of SPION or PVA into naïve mice, an upregulation of pro-inflammatory gene expression was detected in the liver. Administration of SPION or PVA into arthritic mice via i.a. injection did not result in an upregulation in gene expression and also no additional effects were observed on histology. MR imaging and histology showed long-term retention of SPION in the inflamed joint. However, 14 days after the injections no long-term effects were evident for gene expression, histology or serum cytokine concentrations.
  
  
  CONCLUSIONS
  Injection of SPION, either locally or systemically, gives an acute inflammatory response. In the long term, up to 14 days after the injection, while the SPION reside in the joint, no further activating effects of SPION were observed. Hence, we conclude that SPION do not aggravate arthritis and can therefore be used safely to detect joint inflammation by MR imaging.
authors.affiliation: Experimental Rheumatology, Department of Rheumatology, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Eline A
authors.initials: EA
authors.lastname: Vermeij
authors.affiliation: Experimental Rheumatology, Department of Rheumatology, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Marije I
authors.initials: MI
authors.lastname: Koenders
authors.affiliation: Experimental Rheumatology, Department of Rheumatology, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Miranda B
authors.initials: MB
authors.lastname: Bennink
authors.affiliation: Division of Radiology, Geneva University Hospitals, University of Geneva, Faculty of Medicine, Geneva, Switzerland.
authors.forename: Lindsey A
authors.initials: LA
authors.lastname: Crowe
authors.affiliation: Laboratory of Powder Technology, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Lionel
authors.initials: L
authors.lastname: Maurizi
authors.affiliation: Division of Radiology, Geneva University Hospitals, University of Geneva, Faculty of Medicine, Geneva, Switzerland.
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Vallée
authors.affiliation: Laboratory of Powder Technology, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Heinrich
authors.initials: H
authors.lastname: Hofmann
authors.affiliation: Experimental Rheumatology, Department of Rheumatology, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Wim B
authors.initials: WB
authors.lastname: van den Berg
authors.affiliation: Experimental Rheumatology, Department of Rheumatology, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Peter L E M
authors.initials: PL
authors.lastname: van Lent
authors.affiliation: Experimental Rheumatology, Department of Rheumatology, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Fons A J
authors.initials: FA
authors.lastname: van de Loo
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology* / Q000473:pathology; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D005290:Ferric Compounds / Q000378:metabolism*; D007270:Injections, Intra-Articular; D007275:Injections, Intravenous; D008279:Magnetic Resonance Imaging; D058185:Magnetite Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D051379:Mice; D011142:Polyvinyl Alcohol / Q000737:chemistry
chemical_list: D016207:Cytokines; D005290:Ferric Compounds; D058185:Magnetite Nanoparticles; C000499:ferric oxide; D011142:Polyvinyl Alcohol