title: Macrophage endocytosis of superparamagnetic iron oxide nanoparticles: mechanisms and comparison of ferumoxides and ferumoxtran-10.
abstract: OBJECTIVE
  Superparamagnetic iron oxides (SPIO) used as magnetic resonance (MR) contrast agents undergo specific uptake by macrophages. The purpose of this study was first to determine the mechanism of macrophage uptake for Ferumoxides by using competition experiments with specific ligands of scavenger receptors SR-A (I/II) and second, to evaluate and compare the internalization of 2 different contrast agents, Ferumoxides (SPIO) and Ferumoxtran-10 (USPIO: ultrasmall superparamagnetic iron oxide) using macrophages obtained by chemical activation of human monocytic cells.
  
  
  METHODS
  Ferumoxides and Ferumoxtran-10 are 2 MR contrast agents, composed of dextran-coated iron oxide nanoparticles. The endocytosis pathway of Ferumoxides was studied using competition experiments on mouse peritoneal macrophages in the presence of specific ligands of scavenger receptors SR-A (types I and II): polyinosinic acid and fucoidan. In vitro assays using THP-1 (human promonocyte) cells activated into macrophages were performed in the presence of the 2 superparamagnetic nanoparticles. The cellular uptake was determined by measuring the iron content using ICP-AES (inductively coupled plasma-atomic emission spectrometry) and by Prussian blue staining.
  
  
  RESULTS
  In the presence of polyinosinic acid or fucoidan, the endocytosis of Ferumoxides by mouse peritoneal macrophages was inhibited. This inhibition was obtained using 10 microg/mL of scavenger receptor ligands at a concentration of 62.5 microg Fe/mL of SPIO, and a dose-dependent relationship was observed. Without competitors, the percentage of uptake of Ferumoxides by mouse peritoneal macrophages ranged between 3 and 8%. On the human activated monocyte THP-1 cell assay, Ferumoxides underwent a higher macrophage uptake (between 1.1 and 3%) compared with Ferumoxtran-10 (between 0.03 and 0.12%). This difference is attributed to the larger size of Ferumoxides nanoparticles.
  
  
  CONCLUSIONS
  Competition experiments indicate that the cellular uptake of Ferumoxides involves scavenger receptor SR-A-mediated endocytosis. The comparison between Ferumoxides and Ferumoxtran-10 confirms that macrophage uptake of iron oxide nanoparticles depends mainly on the size of these contrast agents.
authors.affiliation: Guerbet-Research Department, Roissy CdG Cedex, France. isabelle.raynal@guerbet-group.com
authors.forename: Isabelle
authors.initials: I
authors.lastname: Raynal
authors.forename: Philippe
authors.initials: P
authors.lastname: Prigent
authors.forename: Sophie
authors.initials: S
authors.lastname: Peyramaure
authors.forename: Abderrahim
authors.initials: A
authors.lastname: Najid
authors.forename: Cécile
authors.initials: C
authors.lastname: Rebuzzi
authors.forename: Claire
authors.initials: C
authors.lastname: Corot
mesh_terms: D000818:Animals; D018955:CD36 Antigens / Q000187:drug effects / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D003287:Contrast Media / Q000737:chemistry / Q000378:metabolism*; D003911:Dextrans; D004705:Endocytosis / Q000502:physiology; D052203:Ferrosoferric Oxide; D006801:Humans; D007375:Interleukin-1 / Q000032:analysis; D007501:Iron / Q000737:chemistry / Q000378:metabolism*; D008262:Macrophage Activation; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D008279:Magnetic Resonance Imaging; D058185:Magnetite Nanoparticles; D051379:Mice; D010087:Oxides / Q000737:chemistry / Q000378:metabolism*; D010316:Particle Size; D011069:Poly I / Q000494:pharmacology; D011134:Polysaccharides / Q000494:pharmacology; D051117:Scavenger Receptors, Class A; D013054:Spectrophotometry, Atomic
chemical_list: D018955:CD36 Antigens; D003287:Contrast Media; D003911:Dextrans; D007375:Interleukin-1; D058185:Magnetite Nanoparticles; D010087:Oxides; D011134:Polysaccharides; D051117:Scavenger Receptors, Class A; C097921:ferumoxtran-10; D011069:Poly I; C007789:fucoidan; D007501:Iron; C065507:ferumoxides; D052203:Ferrosoferric Oxide