title: Causative factors behind poloxamer 188 (Pluronic F68, Flocor)-induced complement activation in human sera. A protective role against poloxamer-mediated complement activation by elevated serum lipoprotein levels.
abstract: Poloxamer 188 is a complex polydisperse mixture of non-ionic macromolecules. Adverse non-IgE-mediated hypersensitivity reactions occur in some individuals following intravenous injection of poloxamer 188-based pharmaceuticals, presumably via complement activation. Here we have delineated potential causal chemical and biological interactive factors behind poloxamer 188-induced complement activation in human serum specimens. We identified the molecular constituents inherent in poloxamer 188 preparations and studied their effect on generation of the two complement split products, SC5b-9 and Bb. Poloxamer 188 activated complement at sub-micellar concentrations and the results indicated the potential involvement of all three known complement activation pathways. The poloxamer-induced rise of SC5b-9 in human sera was abolished in the presence of a recombinant truncated soluble form of complement receptor type 1, thus confirming the role of C3/C5 convertases in the activation process. Poloxamer 188-mediated complement activation is an intrinsic property of these macromolecules and was independent of the degree of sample polydispersity, as opposed to other non-polymeric constituents. Poloxamer 188 preparations also contained unsaturated chains of diblock copolymers capable of generating SC5b-9 in human sera; this effect was terminated following the removal of double bonds by catalytic hydrogenation. By quasi-elastic light scattering, we established interaction between poloxamer and lipoproteins; interestingly, poloxamer-induced rise in SC5b-9 was significantly suppressed when serum HDL and LDL cholesterol levels were increased above normal to mimic two relevant clinical situations. This observation was consistent with previously reported data from patients with abnormal or elevated lipid profiles where no or poor complement activation by poloxamer 188 occurred. Our findings could provide the basis of novel approaches to the prevention of poloxamer-mediated complement activation.
authors.affiliation: Molecular Targeting and Polymer Toxicology Group, School of Pharmacy and Biomolecular Sciences, University of Brighton, Lewis Road, Brighton BN2 4GJ, UK. s.m.moghimi@brighton.ac.uk
authors.forename: S Moein
authors.initials: SM
authors.lastname: Moghimi
authors.forename: A Christy
authors.initials: AC
authors.lastname: Hunter
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Dadswell
authors.forename: Sandor
authors.initials: S
authors.lastname: Savay
authors.forename: Carl R
authors.initials: CR
authors.lastname: Alving
authors.forename: Janos
authors.initials: J
authors.lastname: Szebeni
mesh_terms: D003167:Complement Activation / Q000187:drug effects*; D004342:Drug Hypersensitivity / Q000097:blood* / Q000209:etiology* / Q000276:immunology; D006801:Humans; D008074:Lipoproteins / Q000097:blood*; D020442:Poloxamer / Q000009:adverse effects*; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity
chemical_list: D008074:Lipoproteins; D020442:Poloxamer