PEGylation-associated hemodynamic effects in a rodent model of acute hypersensitivity reaction: Complement activation-mediated mechanisms.

Polyethylene glycol (PEG)-modified nanocomposites may induce acute hypersensitivity reactions (HSR), including complement activation and hypotension, followed by tachyphylaxis with an unknown mechanism. We tested a hypothesis that complement activation mediated hypotension induced by PEGylated magnetic nanoparticles (PEG-MNP) in a rodent model of acute HSR. Blood flow of renal/cremaster vasculature and aortic arch was measured in anesthetized rats using ultrasonic flowmetry or laser speckle contrast imaging. PEG-MNP (250 or 50 nm) induced a temporary reduction in arterial pressure by approximately 30 mmHg, 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 (RVR) with a reduction in the calculated cross-sectional area of renal vessels, whereas the vasodilator acetylcholine decreased both blood pressure and RVR before and after administration of PEG-MNP. Complement depletion by cobra venom factor induced a transient reduction in blood flow and prevented PEG-MNP-induced hemodynamic effects. Proteomic analysis identified much higher complement protein ratio in the hard corona of PEG-MNP vs. MNP in plasma from rats; preexposure of the rats to PEG-MNP or MNP in vivo greatly reduced plasma proteins with high affinity for PEG-MNP. In conclusion, complement activation in the protein corona may mediate PEGylated nanocomposite-induced transient microvascular occlusion that entrains the reversible hemodynamic effects in HSR; complement depletion, at least in part, may mediate tachyphylaxis in response to the 2nd dose of PEGylated nanocomposite. The findings may facilitate predicting or preventing acute HSR to PEGylated nanomedicine or vaccines with growing clinical applications.