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 Despite the tremendous medical need in efficient MRI contrast agents, several dextran SPIO formulations have been withdrawn from the clinical use due to hypersensitivity in patients (Sinerem, Combidex, Feridex).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. This preliminary clinical evaluation demonstrates intravenous delivery of an iron-based contrast agent, resulting in negative enhancement of normal lymph nodes.The complement system is a key component of innate immunity implicated in the neutralization and clearance of invading pathogens.
No significant changes in lymph node signal intensity on T1-weighted spin-echo images were noted at any dose or imaging time point. T2*-weighted gradient echo and T2-weighted spin echo showed significant decrease in the signal intensity of normal lymph nodes at 24 hours after contrast injection at a dose of 1.7 mg Fe/kg. The iron oxide particles were phagocytized by macrophages within the normal functioning lymph nodes, resulting in a dramatic decrease in signal intensity because of magnetic susceptibility effects. Enhancement effects were evaluated as a function of dose, imaging time after contrast administration, and MR pulse sequence. Signal intensities were measured for neck lymph nodes and the adjacent muscle. Image analysis was performed with visually selected regions of interest. T1-, T2-, and proton density-weighted spin-echo images as well as multiplanar gradient-echo and spoiled gradient-echo images were acquired before and 1 hour, 4 hours, and 24 hours after contrast administration. To investigate dextran-coated superparamagnetic iron oxide particles (BMS 180549) as an MR contrast agent for assessing lymph nodes.įive different doses ranging from 0.3 to 1.7 mg Fe/kg were evaluated in five healthy human male subjects as part of a phase 1 clinical study.
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