title: Complement activation by PEGylated liposomes containing prednisolone.
abstract: Infusion of PEGylated liposomes can give rise to hypersensitivity reactions (HSRs) in a relatively large number of patients. Previously it has been shown that these reactions can be caused by activation of the complement (C) system by a negative charge on the anchor molecule of PEG at the liposomal surface. In this study it is tested whether the activation of the C system by PEG-liposomes could be significantly reduced to values comparable to nonreactive liposomal formulations, by changing the PEGylation-profile on the liposomal surface. Therefore, the formation of C activation markers SC5b-9, C3a, C4d and Bb in normal human serum by both prednisolone loaded and empty liposomes with a variation of PEG chain length, PEG surface concentration, PEG anchor molecule and liposomal size was determined using in vitro assays. The tested liposomes caused no or only mild (30%) activation of C except for one formulation wherein the PEG2000 was anchored to cholesterol (CHOL-PEG2000). The latter liposomes caused paralleling rises in SC5b-9 and Bb levels, suggesting excess activation of the alternative pathway. While the relative safety of weak C activator liposomes remains to be confirmed in vivo, the unique, non-charge and non-antibody-mediated direct conversion of C3 by CHOL-PEG2000 liposomes (although argues against the clinical development of these vesicles) opens new opportunities to understand liposomal C activation at the molecular level.
authors.affiliation: Dept. Pharmacy & Pharmacology, Slotervaart Hospital, Louwesweg 6, 1066 EC Amsterdam, The Netherlands. Jolanda.vandenHoven@slz.nl
authors.forename: Jolanda M
authors.initials: JM
authors.lastname: van den Hoven
authors.forename: Reka
authors.initials: R
authors.lastname: Nemes
authors.forename: Josbert M
authors.initials: JM
authors.lastname: Metselaar
authors.forename: Bastiaan
authors.initials: B
authors.lastname: Nuijen
authors.forename: Jos H
authors.initials: JH
authors.lastname: Beijnen
authors.forename: Gert
authors.initials: G
authors.lastname: Storm
authors.forename: Janos
authors.initials: J
authors.lastname: Szebeni
mesh_terms: D000893:Anti-Inflammatory Agents / Q000008:administration & dosage* / Q000737:chemistry; D003167:Complement Activation / Q000187:drug effects*; D006801:Humans; D008055:Lipids / Q000737:chemistry; D008081:Liposomes / Q000008:administration & dosage* / Q000737:chemistry; D011092:Polyethylene Glycols / Q000008:administration & dosage* / Q000737:chemistry; D011239:Prednisolone / Q000008:administration & dosage* / Q000737:chemistry; D044967:Serum / Q000276:immunology*
chemical_list: D000893:Anti-Inflammatory Agents; D008055:Lipids; D008081:Liposomes; D011092:Polyethylene Glycols; D011239:Prednisolone