title: Lysosomal degradation of the carboxydextran shell of coated superparamagnetic iron oxide nanoparticles and the fate of professional phagocytes.
abstract: Contrast agents based on dextran-coated superparamagnetic iron oxide nanoparticles (SPIO) are internalized by professional phagocytes such as hepatic Kupffer cells, yet their role in phagocyte biology remains largely unknown. Here we investigated the effects of the SPIO ferucarbotran on murine Kupffer cells and human macrophages. Intravenous injection of ferucarbotran into mice led to rapid accumulation of the particles in phagocytes and to long-lasting increased iron deposition in liver and kidneys. Macrophages incorporate ferucarbotran in lysosomal vesicles containing α-glucosidase, which is capable of degrading the carboxydextran shell of the ferucarbotran particles. Intravenous injection of ferucarbotran into mice followed by incorporation of the nanoparticles into Kupffer cells triggered apoptosis and the subsequent depletion of Kupffer cells. In macrophages, the proinflammatory cytokine TNF-α increased the apoptosis rate, the reactive oxygen species production and the activation of c-Jun N-terminal kinase elicited by ferucarbotran, which might be mediated by the induction of cytoplasmic phospholipase A2 by TNF-α. Notably, the nanoparticle-induced apoptosis of murine Kupffer cells could be prevented by treatment of the mice with the radical scavenger edaravone. Thus, nanosized carboxydextran-coated SPIO-based contrast agents are retained for extended time periods by liver macrophages, where they elicit delayed cell death, which can be antagonized by a therapeutic radical scavenger.
authors.affiliation: Institute of Pharmacology of Natural Products & Clinical Pharmacology, Helmholtzstr 20, Ulm University, D-89081 Ulm, Germany.
authors.forename: Oleg
authors.initials: O
authors.lastname: Lunov
authors.forename: Tatiana
authors.initials: T
authors.lastname: Syrovets
authors.forename: Carlheinz
authors.initials: C
authors.lastname: Röcker
authors.forename: Kyrylo
authors.initials: K
authors.lastname: Tron
authors.forename: G Ulrich
authors.initials: GU
authors.lastname: Nienhaus
authors.forename: Volker
authors.initials: V
authors.lastname: Rasche
authors.forename: Volker
authors.initials: V
authors.lastname: Mailänder
authors.forename: Katharina
authors.initials: K
authors.lastname: Landfester
authors.forename: Thomas
authors.initials: T
authors.lastname: Simmet
mesh_terms: D000818:Animals; D000983:Antipyrine / Q000031:analogs & derivatives / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D003911:Dextrans / Q000378:metabolism* / Q000493:pharmacokinetics; D000077553:Edaravone; D016166:Free Radical Scavengers / Q000494:pharmacology; D006801:Humans; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D007700:Kinetics; D007728:Kupffer Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism*; D008279:Magnetic Resonance Imaging; D058185:Magnetite Nanoparticles; D051379:Mice; D053758:Nanoparticles / Q000737:chemistry*; D010586:Phagocytes / Q000187:drug effects / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D003911:Dextrans; D016166:Free Radical Scavengers; D058185:Magnetite Nanoparticles; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; C065507:ferumoxides; D000077553:Edaravone; D000983:Antipyrine