title: Superparamagnetic iron oxide nanoparticles impair endothelial integrity and inhibit nitric oxide production.
abstract: Superparamagnetic iron oxide nanoparticles (SPION) are widely used both clinically and experimentally for diverse in vivo applications, such as contrast enhancement in magnetic resonance imaging, hyperthermia and drug delivery. Biomedical applications require particles to have defined physical and chemical properties, and to be stable in biological media. Despite a suggested low cytotoxic action, adverse reactions of SPION in concentrations relevant for biomedical use have not yet been studied in sufficient detail. In the present work we employed Endorem®, dextran-stabilized SPION approved as an intravenous contrast agent, and compared its action to a set of other nanoparticles with potential for magnetic resonance imaging applications. SPION in concentrations relevant for in vivo applications were rapidly taken up by endothelial cells and exhibited no direct cytotoxicity. Electric cell impedance sensing measurements demonstrated that SPION, but not BaSO4/Gd nanoparticles, impaired endothelial integrity, as was confirmed by increased intercellular gap formation in endothelial monolayers. These structural changes induced the subcellular translocation and inhibition of the cytoprotective and anti-atherosclerotic enzyme endothelial NO-synthase and reduced NO production. Lipopolysaccharide-induced inflammatory NO production of macrophages was not affected by SPION. In conclusion, our data suggest that SPION might substantially alter endothelial integrity and function at therapeutically relevant doses, which are not cytotoxic.
authors.affiliation: Department of Pharmacy, Saarland University, Pharmaceutical Biology, Campus C2 2, 66123 Saarbrücken, Germany.
authors.forename: Ksenia
authors.initials: K
authors.lastname: Astanina
authors.affiliation: Department of Pharmacy, Saarland University, Pharmaceutical Biology, Campus C2 2, 66123 Saarbrücken, Germany.
authors.forename: Yvette
authors.initials: Y
authors.lastname: Simon
authors.affiliation: INM - Leibniz Institute for New Materials, Campus D2 2, Saarbrücken, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Cavelius
authors.affiliation: Department of Pharmacy, Saarland University, Pharmaceutical Biology, Campus C2 2, 66123 Saarbrücken, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Petry
authors.affiliation: INM - Leibniz Institute for New Materials, Campus D2 2, Saarbrücken, Germany.
authors.forename: Annette
authors.initials: A
authors.lastname: Kraegeloh
authors.affiliation: Department of Pharmacy, Saarland University, Pharmaceutical Biology, Campus C2 2, 66123 Saarbrücken, Germany. Electronic address: pharm.bio.kiemer@mx.uni-saarland.de.
authors.forename: Alexandra K
authors.initials: AK
authors.lastname: Kiemer
mesh_terms: D016923:Cell Death / Q000187:drug effects; D003911:Dextrans / Q000494:pharmacology*; D004705:Endocytosis / Q000187:drug effects; D011992:Endosomes / Q000187:drug effects / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D057446:Hydrodynamics; D008070:Lipopolysaccharides / Q000494:pharmacology; D058185:Magnetite Nanoparticles; D055806:Microvessels / Q000166:cytology; D053758:Nanoparticles / Q000737:chemistry* / Q000648:ultrastructure; D009569:Nitric Oxide / Q000096:biosynthesis*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010316:Particle Size; D055672:Static Electricity
chemical_list: D003911:Dextrans; D008070:Lipopolysaccharides; D058185:Magnetite Nanoparticles; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; C065507:ferumoxides
keywords: Cell impedance; ECIS®; Endothelial permeability; HUVEC; Nanosafety