In vitro and in vivo complement activation and related anaphylactic effects associated with polyethylenimine and polyethylenimine-graft-poly(ethylene glycol) block copolymers

Complement activation-related pseudoallergy: A stress reaction in blood triggered by nanomedicines and biologicals

“…Further research in this field led to the recognition that the extreme sensitivity of pigs to liposomes (Szebeni et al, 1999(Szebeni et al, , 2000a(Szebeni et al, ,b,c, 2006(Szebeni et al, , 2007aMerkel et al, 2011;Szebeni et al, 2012a,b,c) actually provides a unique model for the 2-10% of man who react to liposomes with mild-to-severe HSRs, and later, to the realization that pigs respond to a broad variety of nano-systems with essentially the same pattern of physiological (hemodynamic, hematological, biochemical and skin) changes, regardless of the chemical composition, size, physicochemical characteristics (charge, surface grafts) or of the trigger particle (Szebeni et al, 2012a,b,c). This then led to the idea that CARPA may fit into the stress theory inasmuch as it provides a uniform defense strategy to cope with a large variety of external harms (McQuillan, 2008).…”

“…One may therefore conclude that liposomal nanomedicines activate C because the immune system considers them as pathogenic viruses, and liposomes do not have a shield that protects them against C attack (Szebeni and Barenholz, 2012). The mechanism of C activation by smaller nanoparticles (d < 10 nm), such as PEGylated polyethylene-imine polymers (Merkel et al, 2011) or micelles formed from CrEL and other polyethoxylated surfactants (PS-80 and PS-20) Weiszhár et al, 2012) is more difficult to explain as they are too small to provide surface platform for the binding of antibodies and/or C proteins. In those cases C activation may involve unconventional direct interaction with C proteins, or, as it was suggested for CrEL, prior interaction with plasma lipoproteins that can lead to the formation of large(er) aggregates .…”

Hemocompatibility testing for nanomedicines and biologicals: predictive assays for complement mediated infusion reactions

“…Further evaluation and refi nement of the recommended assays will require more studies and expert feedback. Nanomedicines/Biologicals Nanomedicines/Biologicals Examples Over the past 13 years or so, we have injected numerous pigs and other animals (dogs and rats) with various liposomes and other nanoparticles (12,26,28,34,45,50,51) . Figure 18 illustrates some features of porcine CARPA that mimic the human liposome reactions and/or help in unveiling their mechanism or prevention.…”

“…Leukocyte count with or without differential, leukocyte activation, haemolysis, reticulocyte count C3a, C 5a, Bb, iC3b, C4d, SC5b-9, CH 50 , C3 convertase, C5 convertase Complement activation guidances by the USA Food and Drug Administration (FDA), European Medicines Agency (EMA) and other regulatory agencies are available, giving recommendations on assays that need to be conducted by the manufacturers to assure the lack of harm caused by blood-exposed foreign material.…”

New Polymer of lactic-co-glycolic acid-modified Polyethylenimine for Nucleic Acid Delivery

“…High-molecular-weight PEI lacks degradable linkages and is not easy to be broken down and excreted from the body. Due to its high positive charges, PEI could disrupt cell membranes [12,13]; and it has the tendency to aggregate red blood cells and bind complement components [14,15]. PEI can induce cell New polymer of lactic-co-glycolic acidmodified polyethylenimine for nucleic acid delivery Jian death through multiple mechanisms including necrosis, apoptosis and autophagy with damaging mitochondrial functions [13,[16][17][18][19][20][21].…”