title: Ferumoxytol nanoparticle uptake in brain during acute neuroinflammation is cell-specific.
abstract: Ferumoxytol ultrasmall superparamagnetic iron oxide nanoparticles can enhance contrast between neuroinflamed and normal-appearing brain tissue when used as a contrast agent for high-sensitivity magnetic resonance imaging (MRI). Here we used an anti-dextran antibody (Dx1) that binds the nanoparticle's carboxymethyldextran coating to differentiate ferumoxytol from endogenous iron and localize it unequivocally in brain tissue. Intravenous injection of ferumoxytol into immune-competent rats that harbored human tumor xenograft-induced inflammatory brain lesions resulted in heterogeneous and lesion-specific signal enhancement on MRI scans in vivo. We used Dx1 immunolocalization and electron microscopy to identify ferumoxytol in affected tissue post-MRI. We found that ferumoxytol nanoparticles were taken up by astrocyte endfeet surrounding cerebral vessels, astrocyte processes, and CD163(+)/CD68(+) macrophages, but not by tumor cells. These results provide a biological basis for the delayed imaging changes seen with ferumoxytol and indicate that ferumoxytol-MRI can be used to assess the inflammatory component of brain lesions in the clinic.
authors.affiliation: Department of Neurology, Oregon Health & Science University, Portland, OR, USA. Electronic address: mcconneh@ohsu.edu.
authors.forename: Heather L
authors.initials: HL
authors.lastname: McConnell
authors.affiliation: Advanced Imaging Research Center, Oregon Health & Science University, Portland, OR, USA. Electronic address: schwartd@ohsu.edu.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Schwartz
authors.affiliation: Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR, USA. Electronic address: brian@brianerichardson.com.
authors.forename: Brian E
authors.initials: BE
authors.lastname: Richardson
authors.affiliation: Department of Pathology, Oregon Health & Science University, Portland, OR, USA. Electronic address: woltjerr@ohsu.edu.
authors.forename: Randall L
authors.initials: RL
authors.lastname: Woltjer
authors.affiliation: Department of Neurology, Oregon Health & Science University, Portland, OR, USA. Electronic address: muldoonl@ohsu.edu.
authors.forename: Leslie L
authors.initials: LL
authors.lastname: Muldoon
authors.affiliation: Department of Neurology, Oregon Health & Science University, Portland, OR, USA; Department of Neurosurgery, Oregon Health & Science University, Portland, OR, USA; Department of Veterans Affairs, Portland Veterans Affairs Medical Center, Portland, OR, USA. Electronic address: neuwelte@ohsu.edu.
authors.forename: Edward A
authors.initials: EA
authors.lastname: Neuwelt
mesh_terms: D000818:Animals; D001921:Brain / Q000473:pathology*; D001932:Brain Neoplasms / Q000000981:diagnostic imaging; D003287:Contrast Media; D052203:Ferrosoferric Oxide / Q000493:pharmacokinetics*; D006801:Humans; D008279:Magnetic Resonance Imaging; D053758:Nanoparticles; D051381:Rats
chemical_list: D003287:Contrast Media; D052203:Ferrosoferric Oxide
keywords: Contrast agents; Iron oxide nanoparticles; MRI; Macrophages; Neuroinflammation