title: Iron nanomedicines induce Toll-like receptor activation, cytokine production and complement activation.
abstract: Approximately a dozen of intravenous iron nanomedicines gained marketing authorization in the last two decades. These products are generally considered as safe, but have been associated with an increased risk for hypersensitivity-like reactions of which the underlying mechanisms are unknown. We hypothesized that iron nanomedicines can trigger the innate immune system. We hereto investigated the physico-chemical properties of ferric gluconate, iron sucrose, ferric carboxymaltose and iron isomaltoside 1000 and comparatively studied their interaction with Toll-like receptors, the complement system and peripheral blood mononuclear cells. Two out of four formulations appeared as aggregates by Scanning Transmission Electron Microscopy analysis and were actively taken up by HEK293T- and peripheral blood mononuclear cells in a cholesterol-dependent manner. These formulations triggered in vitro activation of intracellular Toll-like receptors 3, -7 and -9 in a dose- and serum-dependent manner. In parallel experiments, we determined that these compounds activated the complement system. Finally, we found that uptake of aggregation-prone iron nanomedicines by peripheral blood mononuclear cells in whole blood induced production of the proinflammatory cytokine IL-1β, but not IL-6.
authors.affiliation: Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands. Electronic address: j.j.f.verhoef@uu.nl.
authors.forename: Johan J F
authors.initials: JJF
authors.lastname: Verhoef
authors.affiliation: Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.
authors.forename: A Marit
authors.initials: AM
authors.lastname: de Groot
authors.affiliation: Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
authors.forename: Marc
authors.initials: M
authors.lastname: van Moorsel
authors.affiliation: Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Ritsema
authors.affiliation: Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
authors.forename: Nataliia
authors.initials: N
authors.lastname: Beztsinna
authors.affiliation: Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Coen
authors.initials: C
authors.lastname: Maas
authors.affiliation: Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
authors.forename: Huub
authors.initials: H
authors.lastname: Schellekens
mesh_terms: D002478:Cells, Cultured; D003167:Complement Activation / Q000187:drug effects* / Q000276:immunology; D016207:Cytokines / Q000276:immunology*; D004305:Dose-Response Relationship, Drug; D057809:HEK293 Cells; D006801:Humans; D018836:Inflammation Mediators / Q000276:immunology; D007501:Iron / Q000008:administration & dosage*; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology*; D053768:Metal Nanoparticles / Q000008:administration & dosage*; D051193:Toll-Like Receptors / Q000276:immunology*; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D051193:Toll-Like Receptors; D007501:Iron
keywords: Complement activation; Cytokines; Hypersensitivity-like reactions; Innate immune system; Iron nanomedicines; Toll-like receptors