Journal
INTERNATIONAL JOURNAL OF NANOMEDICINE
Volume 12, Issue -, Pages 3927-3940Publisher
DOVE MEDICAL PRESS LTD
DOI: 10.2147/IJN.S136453
Keywords
iron oxide nanoparticles; human whole blood; complement activation; cytokines; reactive oxygen species; complement inhibitors
Funding
- NanoLab, Norwegian University of Science and Technology
- Research Council of Norway [245963/F50]
- Research Council of Norway Grant through its Centres of Excellence funding scheme [223255/F50]
- National Institutes of Health [AI068730, AI030040]
- European Community's Seventh Frame-work Programme [602699]
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Iron oxide nanoparticles (IONPs) are promising nanomaterials for biomedical applications. However, their inflammatory potential has not been fully established. Here, we used a lepirudin anti-coagulated human whole blood model to evaluate the potential of 10 nm IONPs to activate the complement system and induce cytokine production. Reactive oxygen species and cell death were also assessed. The IONPs activated complement, as measured by C3a, C5a and sC5b-9, and induced the production of pro-inflammatory cytokines in a particle-dose dependent manner, with the strongest response at 10 mu g/mL IONPs. Complement inhibitors at C3 (compstatin analog Cp40) and C5 (eculizumab) levels completely inhibited complement activation and secretion of inflammatory mediators induced by the IONPs. Additionally, blockade of complement receptors C3aR and C5aR1 significantly reduced the levels of various cytokines, indicating that the particle-induced secretion of inflammatory mediators is mainly C5a and C3a mediated. The IONPs did not induce cell death or reactive oxygen species, which further suggests that complement activation alone was responsible for most of the particle-induced cytokines. These data suggest that the lepirudin anti-coagulated human whole blood model is a valuable ex vivo system to study the inflammatory potential of IONPs. We conclude that IONPs induce complement-mediated cytokine secretion in human whole blood.
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