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 activation via calcium-sensitive pathways, but the AP was responsible for the bulk of complement activation and amplification. Activation via the 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.
Highlights
Complement system is a critical component of the innate immunity that comprises ~5% of globulins and is responsible for eliminating and destroying pathogens [1]
We further reported that dextran-coated superparamagnetic iron oxide (SPIO) NWs activate complement in mouse serum via the lectin pathway, but in human serum complement activation is via lectin and alternative pathways (AP) [24,25,26,27,28]
We determined the role of surface modification of dextran-coated iron oxides on the efficiency of complement activation in human sera
Summary
Complement system is a critical component of the innate immunity that comprises ~5% of globulins and is responsible for eliminating and destroying pathogens [1]. It has been reported that crosslinked dextran (Sephadex) enhances complement activation, and substitution of alcohol groups can partially prevent this effect [32,33,34] Despite these advances, the effect of carbohydrate modifications of dextran-coated SPIO on the efficiency of complement activation has not been investigated. The human complement (Figure 2) is triggered by foreign surfaces via the formation of activated C3(H2O) (AP turnover) or via calcium-sensitive pathways (classical or lectin) This activation leads to the initially deposited C3b that associates with factor B to form the AP convertase C3bBb, which cleaves additional C3 molecules. Addition of calcium chelator 10 mM EGTA/2.5 mM Mg2+ [to inhibit operation of calcium-sensitive pathways [36]] dramatically decreased (by 40%) complement activation by NWs prepared with high and intermediate dextran/Fe ratios, but not by NWs prepared with low dextran/Fe ratio (Figure 3A). In order to investigate the contribution of calcium-sensitive pathways in formation of the AP convertase (Figure 2), we measured generation of Bb in sera deficient in C2, which is the critical
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