title: Functionalized superparamagnetic iron oxide nanoparticles provide highly efficient iron-labeling in macrophages for magnetic resonance-based detection in vivo.
abstract: Tracking cells during regenerative cytotherapy is crucial for monitoring their safety and efficacy. Macrophages are an emerging cell-based regenerative therapy for liver disease and can be readily labeled for medical imaging. A reliable, clinically applicable cell-tracking agent would be a powerful tool to study cell biodistribution.
  
  
  
  Using a recently described chemical design, we set out to functionalize, optimize and characterize a new set of superparamagnetic iron oxide nanoparticles (SPIONs) to efficiently label macrophages for magnetic resonance imaging-based cell tracking in vivo.
  
  
  
  A series of cell health and iron uptake assays determined that positively charged SPIONs (+16.8 mV) could safely label macrophages more efficiently than the formerly approved ferumoxide (-6.7 mV; Endorem) and at least 10 times more efficiently than the clinically approved SPION ferumoxytol (-24.2 mV; Rienso). An optimal labeling time of 4 h at 25 µg/mL was demonstrated to label macrophages of mouse and human origin without any adverse effects on cell viability whilst providing substantial iron uptake (>5 pg Fe/cell) that was retained for 7 days in vitro. SPION labeling caused no significant reduction in phagocytic activity and a shift toward a reversible M1-like phenotype in bone marrow-derived macrophages (BMDMs). Finally, we show that SPION-labeled BMDMs delivered via the hepatic portal vein to mice are localized in the hepatic parenchyma resulting in a 50% drop in T2* in the liver. Engraftment of exogenous cells was confirmed via immunohistochemistry up to 3 weeks posttransplantation.
  
  
  
  A positively charged dextran-coated SPION is a promising tool to noninvasively track hepatic macrophage localization for therapeutic monitoring.
authors.affiliation: Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom; UK Regenerative Medicine Platform Safety and Efficacy Hub, United Kingdom.
authors.forename: Jack
authors.initials: J
authors.lastname: Sharkey
authors.affiliation: UK Regenerative Medicine Platform Safety and Efficacy Hub, United Kingdom; MRC Centre for Regenerative Medicine, Little France Drive, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Starkey Lewis
authors.affiliation: UK Regenerative Medicine Platform Safety and Efficacy Hub, United Kingdom; Department of Chemistry, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Michael
authors.initials: M
authors.lastname: Barrow
authors.affiliation: MRC Centre for Regenerative Medicine, Little France Drive, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Salamah M
authors.initials: SM
authors.lastname: Alwahsh
authors.affiliation: Cardiovascular Sciences, Queens Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: June
authors.initials: J
authors.lastname: Noble
authors.affiliation: MRC Centre for Regenerative Medicine, Little France Drive, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Eilidh
authors.initials: E
authors.lastname: Livingstone
authors.affiliation: Edinburgh Preclinical Imaging, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Ross J
authors.initials: RJ
authors.lastname: Lennen
authors.affiliation: Edinburgh Preclinical Imaging, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Maurits A
authors.initials: MA
authors.lastname: Jansen
authors.affiliation: Department of Chemistry, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Jaime Garcia
authors.initials: JG
authors.lastname: Carrion
authors.affiliation: MRC Centre for Drug Safety Science, Ashton Street, University of Liverpool, Liverpool, United Kingdom; European Nanomedicine Characterisation Laboratory (EU-NCL), Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Neill
authors.initials: N
authors.lastname: Liptrott
authors.affiliation: Cardiovascular Sciences, Queens Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Shareen
authors.initials: S
authors.lastname: Forbes
authors.affiliation: UK Regenerative Medicine Platform Safety and Efficacy Hub, United Kingdom; Department of Chemistry, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Dave J
authors.initials: DJ
authors.lastname: Adams
authors.affiliation: UK Regenerative Medicine Platform Safety and Efficacy Hub, United Kingdom; MRC Centre for Drug Safety Science, Ashton Street, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Amy E
authors.initials: AE
authors.lastname: Chadwick
authors.affiliation: UK Regenerative Medicine Platform Safety and Efficacy Hub, United Kingdom; MRC Centre for Regenerative Medicine, Little France Drive, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Stuart J
authors.initials: SJ
authors.lastname: Forbes
authors.affiliation: Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom; UK Regenerative Medicine Platform Safety and Efficacy Hub, United Kingdom.
authors.forename: Patricia
authors.initials: P
authors.lastname: Murray
authors.affiliation: UK Regenerative Medicine Platform Safety and Efficacy Hub, United Kingdom; Department of Chemistry, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Rosseinsky
authors.affiliation: UK Regenerative Medicine Platform Safety and Efficacy Hub, United Kingdom; MRC Centre for Drug Safety Science, Ashton Street, University of Liverpool, Liverpool, United Kingdom. Electronic address: chrissy@liverpool.ac.uk.
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Goldring
authors.affiliation: UK Regenerative Medicine Platform Safety and Efficacy Hub, United Kingdom; MRC Centre for Drug Safety Science, Ashton Street, University of Liverpool, Liverpool, United Kingdom.
authors.forename: B Kevin
authors.initials: BK
authors.lastname: Park
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism; D016026:Bone Marrow Transplantation / Q000379:methods; D002470:Cell Survival; D058948:Cell Tracking / Q000379:methods*; D002478:Cells, Cultured; D003911:Dextrans / Q000737:chemistry* / Q000493:pharmacokinetics; D052203:Ferrosoferric Oxide / Q000737:chemistry / Q000493:pharmacokinetics; D006801:Humans; D007501:Iron / Q000378:metabolism*; D008103:Liver Cirrhosis / Q000628:therapy; D008264:Macrophages / Q000166:cytology* / Q000378:metabolism*; D008279:Magnetic Resonance Imaging / Q000379:methods*; D058185:Magnetite Nanoparticles / Q000737:chemistry*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D014018:Tissue Distribution
chemical_list: D003911:Dextrans; D058185:Magnetite Nanoparticles; D007501:Iron; C065507:ferumoxides; D052203:Ferrosoferric Oxide
keywords: MRI; cell therapy; cell tracking; liver fibrosis; macrophage