Lysosomal degradation of the carboxydextran shell of coated superparamagnetic iron oxide nanoparticles and the fate of professional phagocytes.
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.
Lunov
Oleg
O
Institute of Pharmacology of Natural Products & Clinical Pharmacology, Helmholtzstr 20, Ulm University, D-89081 Ulm, Germany.
Syrovets
Tatiana
T
Röcker
Carlheinz
C
Tron
Kyrylo
K
Nienhaus
G Ulrich
GU
Rasche
Volker
V
Mailänder
Volker
V
Landfester
Katharina
K
Simmet
Thomas
T
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
D003911:Dextrans; D016166:Free Radical Scavengers; D058185:Magnetite Nanoparticles; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; C065507:ferumoxides; D000077553:Edaravone; D000983:Antipyrine