Superparamagnetic iron oxide nanoparticles (SPION) are extensively used for magnetic resonance imaging (MRI) and magnetic particle imaging (MPI), as well as for magnetic fluid hyperthermia (MFH). We here describe a sequential centrifugation protocol to obtain SPION with well-defined sizes from a polydisperse SPION starting formulation, synthesized using the routinely employed co-precipitation technique. Transmission electron microscopy, dynamic light scattering and nanoparticle tracking analyses show that the SPION fractions obtained upon size-isolation are well-defined and almost monodisperse. MRI, MPI and MFH analyses demonstrate improved imaging and hyperthermia performance for size-isolated SPION as compared to the polydisperse starting mixture, as well as to commercial and clinically used iron oxide nanoparticle formulations, such as Resovist ® and Sinerem ®. The size-isolation protocol presented here may help to identify SPION with optimal properties for diagnostic, therapeutic and theranostic applications.
The human body contains 3-4 grams of iron. The majority is utilized in erythrocytes to bind and shuttle oxygen throughout the body. Macrophages in the spleen, bone marrow, and liver recycle iron by taking up senescent erythrocytes and breaking them down to provide iron for processes such as erythropoiesis [5]. The remaining iron is stored in hepatocytes, which serve as a regulatory unit to control the systemic iron level. An alternative regulatory measure to control body iron is adjusting its absorption realized by enterocytes in the duodenum. In enterocytes, iron is either stored to minimize the amount of circulating iron as ferritin or transported to the basal side and released into the bloodstream by Fpn, the only known iron exporter on a cellular level [6,7]. After the release, iron is loaded onto transferrin and distributed safely throughout the body [8]. Transferrin-bound iron is recognized by transferrin receptor (TfR), a membrane-bound protein Trends Trends in in Pharmacological Pharmacological Sciences Sciences Figure 1. Key players in iron metabolism. Iron is absorbed by enterocytes in the duodenum. Non-heme iron in ferric form is reduced by the duodenal cytochrome b (DCYTB) to ferrous iron, which can be transported into cells by divalent metal-ion transporter-1 (DMT1). Ferrous iron is released from enterocytes by ferroportin (Fpn) and oxidized by either membrane-bound hephaestin, ferroxidase, or ceruloplasmin (Cp). In its ferric state, iron can be loaded onto transferrin, which allows for its transportation throughout the body to sites of high iron demand, such as the bone marrow, where the production of erythrocytes takes place. Senescent erythrocytes are recognized and phagocytosed by macrophages and degraded intracellularly. The iron obtained as part of this process is either secreted, stored inside ferritin, or used as part of the labile iron pool. Hepcidin, the master regulator of iron metabolism, is produced and secreted by hepatocytes, where its production is regulated by iron stores and plasma iron levels. Hepcidin binds to Fpn and thereby initiates its internalization and degradation by enterocytes, macrophages, and hepatocytes, resulting in reduced plasma iron levels.
Aims (Ultra) Small superparamagnetic iron oxide nanoparticles, (U)SPIO, are widely used as magnetic resonance imaging contrast media and assumed to be safe for clinical applications in cardiovascular disease. As safety tests largely relied on normolipidemic models, not fully representative of the clinical setting, we investigated the impact of (U)SPIOs on disease-relevant endpoints in hyperlipidemic models of atherosclerosis. Methods and results RAW264.7 foam cells, exposed in vitro to Ferumoxide (dextran-coated SPIO), Ferumoxtran (dextran-coated USPIO), or Ferumoxytol (carboxymethyl dextran-coated USPIO) (all 1 mg Fe/ml) showed increased apoptosis and ROS accumulation for Ferumoxide and Ferumoxtran, whereas Ferumoxytol was tolerated well. Pro-apoptotic (TUNEL+) and pro-oxidant activity of Ferumoxide (0.3 mg Fe/kg) and Ferumoxtran (1 mg Fe/kg) were confirmed in plaque, spleen, and liver of hyperlipidemic ApoE-/- (n = 9/group) and LDLR-/- (n = 9–16/group) mice that had received single IV injections compared to saline-treated controls. Again, Ferumoxytol treatment (1 mg Fe/kg) failed to induce apoptosis or oxidative stress in these tissues. Concomitant antioxidant treatment (EUK-8/EUK-134) largely prevented these effects in vitro (−68%, P < 0.05) and in plaques from LDLR-/- mice (-60%, P < 0.001, n = 8/group). Repeated Ferumoxtran injections of LDLR-/- mice with pre-existing atherosclerosis enhanced plaque inflammation and apoptosis but did not alter plaque size. Strikingly, carotid artery plaques of endarterectomy patients who received Ferumoxtran (2.6 mg Fe/kg) before surgery (n = 9) also showed 5-fold increased apoptosis (18.2 vs. 3.7% respectively; P = 0.004) compared to controls who did not receive Ferumoxtran. Mechanistically, neither coating nor particle size seemed accountable for the observed cytotoxicity of Ferumoxide and Ferumoxtran. Conclusions Ferumoxide and Ferumoxtran, but not Ferumoxytol, induced apoptosis of lipid-laden macrophages in human and murine atherosclerosis, potentially impacting disease progression in patients with advanced atherosclerosis.
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