title: The effect of carboxydextran-coated superparamagnetic iron oxide nanoparticles on c-Jun N-terminal kinase-mediated apoptosis in human macrophages.
abstract: Superparamagnetic iron oxide nanoparticles are frequently used for cell labeling or as diagnostic contrast media, yet studies analyzing their effects on immune cells remain scarce. Here we investigated how nanosized carboxydextran-coated superparamagnetic iron oxide (SPIO) and ultrasmall superparamagnetic iron oxide (USPIO) might affect human macrophages. Within 1 h, both SPIO and USPIO were rapidly taken up by macrophages. Confocal microscopy revealed that after 24 h the particles were almost exclusively localized within the lysosomal compartment. Continued cultivation of the macrophages for several days was associated with apoptosis induction caused by a long-lasting activation of the c-Jun N-terminal kinase (JNK) pathway. JNK activation was due to significantly elevated levels of reactive oxygen species, whereas no TNF-alpha was produced by the macrophages treated with nanoparticles. Compared to SPIO, USPIO induced more pronounced biochemical alterations and cytotoxicity, which could be antagonized by the JNK inhibitor V. Alternatively, treatment of macrophages with Trolox or N-acetyl-L-cysteine, two functionally different scavengers of reactive oxygen species, abolished both the JNK activation and the subsequent cytotoxic effects. These data indicate that nanosized superparamagnetic iron oxide-based contrast media exert cytotoxicity in human macrophages that can be functionally antagonized with radical scavengers.
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: Berthold
authors.initials: B
authors.lastname: Büchele
authors.forename: Xiue
authors.initials: X
authors.lastname: Jiang
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: Paul
authors.initials: P
authors.lastname: Walther
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: D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D020099:Coated Materials, Biocompatible / Q000008:administration & dosage*; D003911:Dextrans / Q000008:administration & dosage*; D052203:Ferrosoferric Oxide / Q000008:administration & dosage*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D058185:Magnetite Nanoparticles; D053758:Nanoparticles / Q000008:administration & dosage*
chemical_list: D020099:Coated Materials, Biocompatible; D003911:Dextrans; D058185:Magnetite Nanoparticles; C097921:ferumoxtran-10; D048031:JNK Mitogen-Activated Protein Kinases; D052203:Ferrosoferric Oxide