Certain Types of Iron Oxide Nanoparticles are Not Suited to Passively Target Inflammatory Cells that Infiltrate the Brain in Response to Stroke

Harms, Christoph; Datwyler, Anna Lena; Wiekhorst, Frank; Trahms, Lutz; Lindquist, Randall L.; Schellenberger, Eyk; Mueller, Susanne; Schütz, Gunnar; Roohi, Farnoosh; Ide, Andreas; Füchtemeier, Martina; Gertz, Karen; Kronenberg, Golo; Harms, Ulrike; Endres, Matthias; Dirnagl, Ulrich; Farr, Tracy D.

doi:10.1038/jcbfm.2013.22

Cited by 30 publications

(16 citation statements)

References 30 publications

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“…This is supported by a rat study, in which only 0.5% of circulating mononuclear cells were positive for iron two hours following intravenous injection of ferumoxytol and protamine sulfate at a dose of 20mg/kg of iron [25]. However, ferumoxytol has an intravascular half-life of approximately 12 hours in humans, 80 minutes in rats and 45 minutes in mice [7, 8, 23]. This means that the longer half-life of ferumoxytol in the human circulation could lead to more iron preloading of macrophages in humans than occurs in mice.…”

Section: Discussionmentioning

confidence: 88%

Ferumoxytol administration does not alter infarct volume or the inflammatory response to stroke in mice

Doyle

Quach

Arceuil

2015

Neuroscience Letters

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Ferumoxytol is an ultrasmall superparamagnetic iron oxide (USPIO) nanoparticle that is FDA approved as an intravenous iron replacement therapy for the treatment of iron deficiency anemia in patients with chronic kidney disease. Ferumoxytol has also been used as a contrast agent for cerebral blood volume mapping by magnetic resonance imaging (MRI), which suggests it could be used for imaging hemodynamic abnormalities after stroke. However, circulating macrophages can internalize USPIOs, and recent data indicate that the accumulation of iron in macrophages can lead them to adopt the M1 pro-inflammatory phenotype. Therefore, the uptake of intravenously administered iron particles by circulating macrophages that home to the stroke core could potentially alter the inflammatory response to stroke. To test this possibility in vivo we administered a dose of ferumoxytol previously used to obtain cerebral blood volume maps in healthy humans by steady-state susceptibility contrast (SSC) MRI to BALB/cJ mice 48 hours after stroke and examined cytokine levels, microglial/macrophage activation, and lesion volume in the brain 5 days later. Treatment with ferumoxytol did not lead to any differences in these parameters. These data indicate that the use of ferumoxytol as a contrast agent for brain imaging after stroke does not alter the inflammatory response to stroke in mice, and is therefore unlikely to do so in human subjects.

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Section: Discussionmentioning

confidence: 88%

Ferumoxytol administration does not alter infarct volume or the inflammatory response to stroke in mice

Doyle

Quach

Arceuil

2015

Neuroscience Letters

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“…At 7 days after stroke, we detected iron deposition using the Accustain Iron Kit (Sigma-Aldrich)by following manufacture’s instructions [13, 14]. For semi-quantitative analysis, on three coronal sections (20-μm thick, at 2-mm interval) at −0.8, −2.8 and −4.8mm from bregma (the maximal brain infarct area), five consecutive fields (×200 magnification) along with subcortical peri-infarct area of each section(totally 15 fields per brain) were digitized for determining iron pigment (blue color).…”

Section: Methodsmentioning

confidence: 99%

Low dose tPA plus annexin A2 combination attenuates tPA delayed treatment- associated hemorrhage and improves recovery in rat embolic focal stroke

Jiang

Fan

et al. 2015

Neuroscience Letters

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We previously have shown that tissue type plasminogen activator (tPA) in combination with its receptor annexin A2 (rA2) protein significantly improved tPA thrombolytic efficacy. In this study we aimed to examine the therapeutic effects of the combination when treated at delayed 4-hourwindow after stroke compared to standard conventional tPA alone in an embolic focal stroke rat model. We compared effects of intravenous tPA alone (10mg/kg) versus a combination of low-dose tPA (5mg/kg) plus 10 mg/kg rA2. Totally 152 rats were used. Our results showed that: (1) at 24 hours after stroke, the combination slightly reduced brain infarction compared to saline (9.2% reduction), and tPA (7.4% reduction), although the reductions did not reach statistical significance; while the combination significantly reduced (22.2% reduction) the conventional tPA-elevated intracerebral hemorrhagic (ICH) transformation; (2)at 7 days after stroke, the combination significantly attenuated conventional tPA alone-elevated iron deposition at peri-lesion area (68.2% reduction); (3) at 28 days after stroke, the combination significantly improved performance of adhesive tape-removal test, which was accompanied by asignificantly higher microvessel density at peri-infarct areas compared to conventional tPA alone group. In conclusion, compared to conventional tPA alone, when treated at delayed 4-hour after stroke, the combination of low-dose tPA plus rA2 therapy provides a safer profile by lowering risk of ICH transformation and improves neurological function recovery after stroke.

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“…This correlation was confirmed on the cellular level where CLIO uptake by macrophages correlated significantly with the clinical score. Iron oxide nanoparticle imaging has been performed in a wide variety of diseases (16,17,(33)(34)(35), but apart from liver imaging (36), iron oxide imaging has not yet been translated into clinical practice, partially because of economic, safety, and technical reasons (37)(38)(39)(40). However, imaging of inflammation is of major clinical interest.…”

Section: Discussionmentioning

confidence: 99%

In vivo nanoparticle imaging of innate immune cells can serve as a marker of disease severity in a model of multiple sclerosis

Kirschbaum

Sonner

Zeller

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Innate immune cells play a key role in the pathogenesis of multiple sclerosis and experimental autoimmune encephalomyelitis (EAE). Current clinical imaging is restricted to visualizing secondary effects of inflammation, such as gliosis and blood-brain barrier disruption. Advanced molecular imaging, such as iron oxide nanoparticle imaging, can allow direct imaging of cellular and molecular activity, but the exact cell types that phagocytose nanoparticles in vivo and how phagocytic activity relates to disease severity is not well understood. In this study we used MRI to map inflammatory infiltrates using high-field MRI and fluorescently labeled cross-linked iron oxide nanoparticles for cell tracking. We confirmed nanoparticle uptake and MR detectability ex vivo. Using in vivo MRI, we identified extensive nanoparticle signal in the cerebellar white matter and circumscribed cortical gray matter lesions that developed during the disease course (4.6-fold increase of nanoparticle accumulation in EAE compared with healthy controls, P < 0.001). Nanoparticles showed good cellular specificity for innate immune cells in vivo, labeling activated microglia, infiltrating macrophages, and neutrophils, whereas there was only sparse uptake by adaptive immune cells. Importantly, nanoparticle signal correlated better with clinical disease than conventional gadolinium (Gd) imaging (r, 0.83 for nanoparticles vs. 0.71 for Gd-imaging, P < 0.001). We validated our approach using the Food and Drug Administration-approved iron oxide nanoparticle ferumoxytol. Our results show that noninvasive molecular imaging of innate immune responses can serve as an imaging biomarker of disease activity in autoimmune-mediated neuroinflammation with potential clinical applications in a wide range of inflammatory diseases.MRI | nanoparticle imaging | USPIO | multiple sclerosis | EAE

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Certain Types of Iron Oxide Nanoparticles are Not Suited to Passively Target Inflammatory Cells that Infiltrate the Brain in Response to Stroke

Cited by 30 publications

References 30 publications

Ferumoxytol administration does not alter infarct volume or the inflammatory response to stroke in mice

Ferumoxytol administration does not alter infarct volume or the inflammatory response to stroke in mice

Low dose tPA plus annexin A2 combination attenuates tPA delayed treatment- associated hemorrhage and improves recovery in rat embolic focal stroke

In vivo nanoparticle imaging of innate immune cells can serve as a marker of disease severity in a model of multiple sclerosis

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