title: Mechanisms of complement activation by dextran-coated superparamagnetic iron oxide (SPIO) nanoworms in mouse versus human serum.
abstract: BACKGROUND
  The complement system is a key component of innate immunity implicated in the neutralization and clearance of invading pathogens. Dextran coated superparamagnetic iron oxide (SPIO) nanoparticle is a promising magnetic resonance imaging (MRI) contrast agent. However, dextran SPIO has been associated with significant number of complement-related side effects in patients and some agents have been discontinued from clinical use (e.g., Feridex™). In order to improve the safety of these materials, the mechanisms of complement activation by dextran-coated SPIO and the differences between mice and humans need to be fully understood.
  
  
  METHODS
  20 kDa dextran coated SPIO nanoworms (SPIO NW) were synthesized using Molday precipitation procedure. In vitro measurements of C3 deposition on SPIO NW using sera genetically deficient for various components of the classical pathway (CP), lectin pathway (LP) or alternative pathway (AP) components were used to study mechanisms of mouse complement activation. In vitro measurements of fluid phase markers of complement activation C4d and Bb and the terminal pathway marker SC5b-C9 in normal and genetically deficient sera were used to study the mechanisms of human complement activation. Mouse data were analyzed by non-paired t-test, human data were analyzed by ANOVA followed by multiple comparisons with Student-Newman-Keuls test.
  
  
  RESULTS
  In mouse sera, SPIO NW triggered the complement activation via the LP, whereas the AP contributes via the amplification loop. No involvement of the CP was observed. In human sera the LP together with the direct enhancement of the AP turnover was responsible for the complement activation. In two samples out of six healthy donors there was also a binding of anti-dextran antibodies and C1q, suggesting activation via the CP, but that did not affect the total level of C3 deposition on the particles.
  
  
  CONCLUSIONS
  There were important differences and similarities in the complement activation by SPIO NW in mouse versus human sera. Understanding the mechanisms of immune recognition of nanoparticles in mouse and human systems has important preclinical and clinical implications and could help design more efficient and safe nano-formulations.
authors.affiliation: Division of Rheumatology, School of Medicine, University of Colorado Anschutz Medical Campus, 1775 Aurora Court, Aurora, CO 80045, USA. Nirmal.Banda@ucdenver.edu.
authors.forename: Nirmal K
authors.initials: NK
authors.lastname: Banda
authors.affiliation: Division of Rheumatology, School of Medicine, University of Colorado Anschutz Medical Campus, 1775 Aurora Court, Aurora, CO 80045, USA. Gaurav.Mehta@ucdenver.edu.
authors.forename: Gaurav
authors.initials: G
authors.lastname: Mehta
authors.affiliation: Moores UCSD Cancer Center, UC San Diego, 3855 Health Sciences Drive, La Jolla, CA, 92093, USA. yschao@gmail.com.
authors.forename: Ying
authors.initials: Y
authors.lastname: Chao
authors.affiliation: The Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, 12850 East Montview Blvd., Aurora, CO, 80045, USA. GUANKUI.WANG@UCDENVER.EDU.
authors.forename: Guankui
authors.initials: G
authors.lastname: Wang
authors.affiliation: The Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, 12850 East Montview Blvd., Aurora, CO, 80045, USA. Swetha.Inturi@ucdenver.edu.
authors.forename: Swetha
authors.initials: S
authors.lastname: Inturi
authors.affiliation: Centre for Complement & Inflammation Research (CCIR), Division of Immunology and Inflammation, Department of Medicine, Imperial College London Hammersmith Campus, Du Cane Road, London, W12 ONN, UK. l.fossati@imperial.ac.uk.
authors.forename: Liliane
authors.initials: L
authors.lastname: Fossati-Jimack
authors.affiliation: Centre for Complement & Inflammation Research (CCIR), Division of Immunology and Inflammation, Department of Medicine, Imperial College London Hammersmith Campus, Du Cane Road, London, W12 ONN, UK. m.botto@imperial.ac.uk.
authors.forename: Marina
authors.initials: M
authors.lastname: Botto
authors.affiliation: Centre for Pharmaceutical Nanotechnology and Nanotoxicology, Department of Pharmacy, Faculty of Health and Medical Sciences, Universitetsparken 2, University of Copenhagen, DK-2100, Copenhagen, Denmark. linping.wu@sund.ku.dk.
authors.forename: LinPing
authors.initials: L
authors.lastname: Wu
authors.affiliation: Centre for Pharmaceutical Nanotechnology and Nanotoxicology, Department of Pharmacy, Faculty of Health and Medical Sciences, Universitetsparken 2, University of Copenhagen, DK-2100, Copenhagen, Denmark. moien.moghimi@sund.ku.dk.|NanoScience Centre, University of Copenhagen, DK-2100, Copenhagen, Denmark. moien.moghimi@sund.ku.dk.
authors.forename: Seyed Moein
authors.initials: SM
authors.lastname: Moghimi
authors.affiliation: The Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, 12850 East Montview Blvd., Aurora, CO, 80045, USA. dmitri.simberg@ucdenver.edu.
authors.forename: Dmitri
authors.initials: D
authors.lastname: Simberg
mesh_terms: D000328:Adult; D000818:Animals; D015415:Biomarkers / Q000097:blood; D003167:Complement Activation / Q000187:drug effects*; D003170:Complement Pathway, Alternative / Q000187:drug effects; D003171:Complement Pathway, Classical / Q000187:drug effects; D037582:Complement Pathway, Mannose-Binding Lectin / Q000187:drug effects; D003165:Complement System Proteins / Q000235:genetics / Q000378:metabolism; D003287:Contrast Media / Q000494:pharmacology*; D003911:Dextrans / Q000494:pharmacology*; D006801:Humans; D058185:Magnetite Nanoparticles; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013045:Species Specificity; D013499:Surface Properties
chemical_list: D015415:Biomarkers; D003287:Contrast Media; D003911:Dextrans; D058185:Magnetite Nanoparticles; D003165:Complement System Proteins; C065507:ferumoxides