Hemodynamic Characteristics of Acute Hypersensitivity Reaction Induced by PEGylated Nanocomposite in Rats: Mechanism at the Nano-Bio Interface

BackgroundPolyethylene glycol (PEG)-modified nanocomposites may induce acute hypersensitivity reactions (HSR), including complement activation and hypotension, followed by tachyphylaxis with an unknown mechanism. We established a rodent model of acute HSR, and hypothesized that the formation of protein corona with a composition specific to PEGylated nanoparticles induces an acute and transient microvascular occlusion that entrains the hemodynamic effects. MethodsHemodynamic parameters of renal and cremaster vasculature were measured in anesthetized rats using ultrasonic flowmetry and laser speckle contrast imaging, respectively. Proteomic analysis on the hard corona of dextran-coated magnetic nanoparticles (MNP) with and without PEGylation was conducted after incubation of the nanoparticles with plasma from rats. ResultsPEG-MNP iv. induced a temporary reduction by approximately 30 mmHg in arterial pressure, with significant reduction in renal/cremaster blood flow and cardiac output, followed by tachyphylaxis and thrombocytopenia. PEG-MNP, but not pristine MNP, significantly increased renal vascular resistance with a reduction in the calculated cross-sectional area of renal vessels, suggesting microvascular occlusion. In contrast, the vasodilator acetylcholine decreased both blood pressure and vascular resistance before and after administration of PEG-MNP, suggesting an intact endothelium. Complement depletion by cobra venom factor induced a transient reduction in blood flow and prevented PEG-MNP-induced hemodynamic effects, suggesting an important role of complement activation. Proteomic analysis identified much higher complement proteins in the hard corona of PEG-MNP vs. MNP in plasma from rats; preexposure of rats to PEG-MNP or MNP in vivo greatly reduced plasma proteins with high affinity for PEG-MNP. The results suggest that complement depletion may mediate tachyphylaxis in response to the 2nd dose of PEG-MNP. ConclusionPEGylated nanocomposites-induced complement activation in the protein corona may trigger the hemodynamic effects and subsequent pathophysiological responses in HSR of rats. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=150 SRC="FIGDIR/small/642931v1_ufig1.gif" ALT="Figure 1"> View larger version (76K): org.highwire.dtl.DTLVardef@1554185org.highwire.dtl.DTLVardef@40b9d0org.highwire.dtl.DTLVardef@1671c5borg.highwire.dtl.DTLVardef@76dbb5_HPS_FORMAT_FIGEXP M_FIG C_FIG PEGylated magnetic nanoparticles (PEG-MNPs)-induced complement activation and platelet aggregation mediate the systemic increase in resistance of microvessels in rats.