title: The effect of static magnetic fields on the aggregation and cytotoxicity of magnetic nanoparticles.
abstract: Biomedical applications of magnetic nanoparticles (MNP), including superparamagnetic nanoparticles, have expanded dramatically in recent years. Systematic and standardized cytotoxicity assessment to ensure the biosafety and biocompatibility of those applications is compulsory. We investigated whether exposure to static magnetic field (SMF) from e.g. magnetic resonance imaging (MRI) could affect the cytotoxicity of superparamagnetic iron oxide (SPIO) nanoparticles using mouse hepatocytes and ferucarbotran, a liver-selective MRI contrast agent as a model system. We show that while the SPIO satisfied the conventional cytotoxicity assessment, clinical doses combined with SMF exposure exerts synergistic adverse effects such as reduced cell viability, apoptosis, and cell cycle aberrations on hepatocytes in vitro and in vivo. Concomitant treatments with the SPIO and SMF generated SPIO aggregates, which demonstrated enhanced cellular uptake, was sufficient to induce the cytotoxicity without further SMF, emphasizing that the SPIO aggregates were the predominant source of the cytotoxicity. Interestingly, the apoptotic effect was dependent on levels of reactive oxygen species (ROS) and SPIO uptake while the reduced cell viability was independent of these factors. Moreover, long-term monitoring showed a significant increase in multinuclear giant cells in the cells concomitantly treated with the SPIO and SMF compared with the control. The results demonstrate that the SPIO produces unidentified cytotoxicity on liver in the presence of SMF and the SPIO aggregates predominantly exert the effect. Since aggregation of MNP in biological milieu in the presence of strong SMF is inevitable, a fundamentally different approach to surface fabrication is essential to increase the biocompatibility of MNP.
authors.affiliation: Department of Biology, Teachers' College, Kyungpook National University, Daegu 702-701, Korea.
authors.forename: Ji-Eun
authors.initials: JE
authors.lastname: Bae
authors.forename: Man-Il
authors.initials: MI
authors.lastname: Huh
authors.forename: Byung-Kyu
authors.initials: BK
authors.lastname: Ryu
authors.forename: Ji-Yeon
authors.initials: JY
authors.lastname: Do
authors.forename: Seong-Uk
authors.initials: SU
authors.lastname: Jin
authors.forename: Myung-Jin
authors.initials: MJ
authors.lastname: Moon
authors.forename: Jae-Chang
authors.initials: JC
authors.lastname: Jung
authors.forename: Yongmin
authors.initials: Y
authors.lastname: Chang
authors.forename: Eungseok
authors.initials: E
authors.lastname: Kim
authors.forename: Sung-Gil
authors.initials: SG
authors.lastname: Chi
authors.forename: Gang-Ho
authors.initials: GH
authors.lastname: Lee
authors.forename: Kwon-Seok
authors.initials: KS
authors.lastname: Chae
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D003911:Dextrans / Q000737:chemistry / Q000633:toxicity; D004705:Endocytosis / Q000187:drug effects; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D060526:Magnetic Fields; D008279:Magnetic Resonance Imaging; D058185:Magnetite Nanoparticles / Q000737:chemistry* / Q000633:toxicity* / Q000648:ultrastructure; D051379:Mice; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D003911:Dextrans; D058185:Magnetite Nanoparticles; D017382:Reactive Oxygen Species; C065507:ferumoxides