(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... Show more(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.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.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. Show less
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... Show moreAims (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 normolipidaemic models, not fully representative of the clinical setting, we investigated the impact of (U)SPIOs on disease-relevant endpoints in hyperlipidaemic 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 (CM) dextran-coated USPIO] (all 1 mg Fe/mL) showed increased apoptosis and reactive oxygen species 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 hyperlipidaemic ApoE(-/-) (n = 9/group) and LDLR-/- (n = 9-16/group) mice that had received single IV injections compared with 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 five-fold increased apoptosis (18.2 vs. 3.7%, respectively; P = 0.004) compared with 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. Show less
Segers, F.M.E.; Adel, B. den; Bot, I.; Graaf, L.M. van der; Veer, E.P. van der; Gonzalez, W.; ... ; Biessen, E.A.L. 2013
Een effectieve diagnose voor hart- en vaatziekten kan op dit moment pas gesteld worden als de ziekte zich al in een vergevorderd stadium bevindt of als er klinische symptomen (beroerte) zijn... Show moreEen effectieve diagnose voor hart- en vaatziekten kan op dit moment pas gesteld worden als de ziekte zich al in een vergevorderd stadium bevindt of als er klinische symptomen (beroerte) zijn opgetreden. Tijdens mijn promotieonderzoek heb ik in samenwerking met de farmaceutische industrie (Guerbet) aandacht besteed aan het synthetiseren en valideren van kleine eiwitten die specifiek binden en opgenomen worden door receptoren waarvan aangetoond is dat deze verhoogd tot expressie komen of een specifieke rol spelen in atherosclerose. Dit heeft geleid tot de synthese van 2 kleine eiwitten (PP1 en NP31) die specifiek gericht zijn tegen respectievelijk de scavenger receptor en de CD40 receptor. De scavenger receptor komt verhoogd tot expressie op macrofagen en zorgt voor de verwijdering van slecht cholesterol uit de bloedbaan en vaatwand. De CD40 receptor speelt een belangrijke rol bij de initiatie en in standhouding van de ontstekingsreactie bij atherosclerose. Het onderzoek beschreven in dit proefschrift geeft nieuwe inzichten in mogelijke toepassingen van synthetisch eiwitten die specifiek binden aan receptoren die belangrijk zijn tijdens de ontwikkeling van hart- en vaatziekten. De verschillende synthetische liganden kunnen gezien worden als potenti_le kandidaat-eiwitten voor verbeterde beeldvormingtechnieken van atherosclerotische plaques. Show less
