Īctivation of the complement plays a major role in the immune recognition of nanoparticles and pathogens. In humans, five different sugar recognition molecules have been identified that are able to initiate the LP: MBL, M-, L-, and H-ficolins and collectin 11 (CL11 or CL-K1), but the downstream activation of the classical C3 convertase is believed to be similar in mice and humans. In mice, the activation is primarily triggered via initial binding of mannose-binding lectin -A and -C or ficolin A to carbohydrates on the pathogen surface, leading to activation of MBL-associated serum protease MASP-2 and formation of C4bC2a, the C3 convertase. Lectin pathway (LP) is somewhat different in mice vs. More C3b is formed through the alternative pathway (AP) via the formation of alternative C3 convertase C3bBb. C4bC2a cleaves C3 into C3a and C3b, and the latter covalently attaches via highly reactive thioester group to hydroxyls and amines on the foreign surface. The CP activation is triggered via initial binding of IgG or IgM to the pathogen surface, followed by binding and activation of C1q component and formation of C4bC2a, a C3 convertase. Activation of the complement on the foreign surface takes place via either the classical pathway (CP), the lectin pathway (LP) or the alternative pathway (AP). The complement system accounts for about 5% of globulins in serum and is responsible for recognition, elimination and destruction of pathogens. In order to design contrast agents with reduced toxicity and improved pharmacokinetics, a basic understanding of immune recognition of these materials in both mouse (preclinical) and human (clinical) systems of paramount importance. Another problem of these nanomaterials is the propensity of dextran SPIO for liver and spleen clearance, which limits imaging to macrophage-rich organs. Despite the tremendous medical need in efficient MRI contrast agents, several dextran SPIO formulations have been withdrawn from the clinical use due to hypersensitivity in patients (Sinerem, Combidex, Feridex). Dextran SPIO consists of magnetite-maghemite (Fe 3O 4 and γ-Fe 2O 3) crystalline cores of 3–10 nm size coated with dextran or carboxymethyl dextran. Superparamagnetic iron oxide (SPIO) is one of the most widely cited metal oxide nanoparticle that has been used as magnetic resonance imaging (MRI) contrast agent alone and as a component of multifunctional nanomedicines. Understanding the mechanisms of immune recognition of nanoparticles in mouse and human systems has important preclinical and clinical implications and could help design more efficient and safe nano-formulations. There were important differences and similarities in the complement activation by SPIO NW in mouse versus human sera. In two samples out of six healthy donors there was also a binding of anti-dextran antibodies and C1q, suggesting activation via the CP, but that did not affect the total level of C3 deposition on the particles. In human sera the LP together with the direct enhancement of the AP turnover was responsible for the complement activation. In mouse sera, SPIO NW triggered the complement activation via the LP, whereas the AP contributes via the amplification loop. Mouse data were analyzed by non-paired t-test, human data were analyzed by ANOVA followed by multiple comparisons with Student-Newman-Keuls test. In vitro measurements of fluid phase markers of complement activation C4d and Bb and the terminal pathway marker SC5b-C9 in normal and genetically deficient sera were used to study the mechanisms of human complement activation. In vitro measurements of C3 deposition on SPIO NW using sera genetically deficient for various components of the classical pathway (CP), lectin pathway (LP) or alternative pathway (AP) components were used to study mechanisms of mouse complement activation. MethodsĢ0 kDa dextran coated SPIO nanoworms (SPIO NW) were synthesized using Molday precipitation procedure. In order to improve the safety of these materials, the mechanisms of complement activation by dextran-coated SPIO and the differences between mice and humans need to be fully understood. However, dextran SPIO has been associated with significant number of complement-related side effects in patients and some agents have been discontinued from clinical use (e.g., Feridex™). Dextran coated superparamagnetic iron oxide (SPIO) nanoparticle is a promising magnetic resonance imaging (MRI) contrast agent. The complement system is a key component of innate immunity implicated in the neutralization and clearance of invading pathogens.
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