title: Activation of Human Complement System by Dextran-Coated Iron Oxide Nanoparticles Is Not Affected by Dextran/Fe Ratio, Hydroxyl Modifications, and Crosslinking.
abstract: While having tremendous potential as therapeutic and imaging tools, the clinical use of engineered nanoparticles has been associated with serious safety concerns. Activation of the complement cascade and the release of proinflammatory factors C3a and C5a may contribute to infusion-related reactions, whereas opsonization with C3 fragments promotes rapid recognition and clearance of nanomaterials by mononuclear phagocytes. We used dextran-coated superparamagnetic iron oxide nanoparticles (SPIO), which are potent activators of the complement system, to study the role of nanoparticle surface chemistry in inciting complement in human serum. Using complement inhibitors and measuring levels of fluid phase markers (sC5b-9, C5a, and Bb), we found that the majority of human complement activation by SPIO is through the alternative pathways (AP). SPIO prepared with high dextran/iron ratio showed some complement activationviacalcium-sensitive pathways, but the AP was responsible for the bulk of complement activation and amplification. Activationviathe AP required properdin, the positive regulator of the alternative C3bBb convertase. Modification of sugar alcohols of dextran with alkylating, acylating, or crosslinking agents did not overcome complement activation and C3 opsonization. These data demonstrate that human complement activation is independent of dextran modification of SPIO and suggest a crucial role of the AP in immune recognition of nano-assemblies in human serum.
authors: Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus , Aurora, CO , USA.
authors: Guankui
authors: G
authors: Wang
authors: Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, USA; Department of Gastrointestinal Surgery, China-Japan Union Hospital, Jilin University, Changchun, China.
authors: Fangfang
authors: F
authors: Chen
authors: Division of Rheumatology, School of Medicine, University of Colorado Denver , Aurora, CO , USA.
authors: Nirmal K
authors: NK
authors: Banda
authors: Division of Rheumatology, School of Medicine, University of Colorado Denver , Aurora, CO , USA.
authors: V Michael
authors: VM
authors: Holers
authors: Nanomedicine Laboratory, Department of Pharmacy, Centre for Pharmaceutical Nanotechnology and Nanotoxicology, University of Copenhagen , Copenhagen , Denmark.
authors: LinPing
authors: L
authors: Wu
authors: School of Medicine, Pharmacy and Health, Durham University , Durham , UK.
authors: S Moein
authors: SM
authors: Moghimi
authors: Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus , Aurora, CO , USA.
authors: Dmitri
authors: D
authors: Simberg
keywords: alternative pathway of complement; complement C3; complement system proteins; dextran; iron oxide nanoparticles; lectin pathway; properdin