title: Relationship between the concentration of anti-polyethylene glycol (PEG) immunoglobulin M (IgM) and the intensity of the accelerated blood clearance (ABC) phenomenon against PEGylated liposomes in mice.
abstract: PEGylation, which is the surface modification of nanocarriers with polyethylene glycol (PEG), has increased the circulation time and reduced the immunogenic responses to nanocarriers. However, many reports have demonstrated that the intravenous injection of sterically stabilized PEGylated liposome (SL) causes an accelerated blood clearance (ABC) of subsequent doses via anti-PEG immunoglobulin M (IgM)-mediated complement activation. In the present study, the relationships between serum anti-PEG IgM concentration, the intensity of complement activation and the hepatic clearance of SL were quantitatively investigated for their role in the ABC phenomenon. Interestingly, with increasing serum anti-PEG IgM concentrations, the intensity of complement activation increased linearly, while the intensity of the hepatic clearance of SL was increased and then saturated. In addition, only 15-17% of anti-PEG IgM in blood circulation induced by SL at different doses was associated with a second dose SL. The present results indicate that it is the hepatic uptake of SL that is the limiting step in the ABC phenomenon, rather than the association of anti-PEG IgM to the SL and a subsequent complement activation.
authors.affiliation: Department of Pharmacokinetics and Biopharmaceutics, Subdivision of Biopharmaceutical Sciences, Institute of Health Biosciences, The University of Tokushima.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Hashimoto
authors.forename: Taro
authors.initials: T
authors.lastname: Shimizu
authors.forename: Amr Selim
authors.initials: AS
authors.lastname: Abu Lila
authors.forename: Tatsuhiro
authors.initials: T
authors.lastname: Ishida
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kiwada
mesh_terms: D000818:Animals; D003165:Complement System Proteins / Q000378:metabolism*; D004317:Doxorubicin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000276:immunology / Q000493:pharmacokinetics / Q000494:pharmacology; D004337:Drug Carriers / Q000009:adverse effects; D007075:Immunoglobulin M / Q000097:blood*; D007275:Injections, Intravenous; D008081:Liposomes; D008099:Liver / Q000378:metabolism*; D008297:Male; D008807:Mice, Inbred BALB C; D053758:Nanoparticles; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D004337:Drug Carriers; D007075:Immunoglobulin M; D008081:Liposomes; C506643:liposomal doxorubicin; D011092:Polyethylene Glycols; D004317:Doxorubicin; D003165:Complement System Proteins