title: Hydrophobic blocks of PEG-conjugates play a significant role in the accelerated blood clearance (ABC) phenomenon.
abstract: Injections of poly(ethylene glycol)-modified liposomes (PEG-liposomes) cause rapid clearance of the second dose of PEG-liposomes. This phenomenon is known as the accelerated blood clearance (ABC) phenomenon. Previous studies have suggested that PEG-specific IgM (anti-PEG IgM) can play a major role in the ABC phenomenon. In our previous study, however, a PEG-shell-possessing polymeric micelle with hydrophilic inner core (PEG-P(Lys-DOTA-Gd) micelle) did not induce the ABC phenomenon nor the IgM responses, and exhibited no change in its plasma concentration in PEG-liposome-injected mice. In the present paper, we studied the ABC-phenomenon in more detail by comparing the behaviors between PEG-liposomes, PEG-P(Lys-DOTA-Gd) micelle, and hydrophobic-core-possessing PEG-PBLA micelles. We demonstrated that the PEG-PBLA micelle induced similar IgM responses as observed in PEG-liposome; however, the second dose of PEG-PBLA micelle exhibited no decreases in their plasma concentration, while the second dose of PEG-liposome did exhibit rapid clearances. Furthermore, we did not observe any PEG main chain specific IgM in PEG-liposome injected mice by sandwich ELISA which can measure more specific IgM to the PEG main chain theoretically. These results suggested that the induced IgM recognizes an interface between PEG chain and hydrophobic chain, rather than PEG main chain, and the anti-PEG IgM hypothesis should be re-evaluated.
authors.affiliation: Medical Engineering Laboratory, Research Center for Medical Science, The Jikei University School of Medicine, 3-25-8, Nishi-shinbashi, Minato-ku, Tokyo 105-8461, Japan.
authors.forename: Kouichi
authors.initials: K
authors.lastname: Shiraishi
authors.forename: Mikiko
authors.initials: M
authors.lastname: Hamano
authors.forename: Huili
authors.initials: H
authors.lastname: Ma
authors.forename: Kumi
authors.initials: K
authors.lastname: Kawano
authors.forename: Yoshie
authors.initials: Y
authors.lastname: Maitani
authors.forename: Taiki
authors.initials: T
authors.lastname: Aoshi
authors.forename: Ken J
authors.initials: KJ
authors.lastname: Ishii
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yokoyama
mesh_terms: D000818:Animals; D004797:Enzyme-Linked Immunosorbent Assay; D005682:Gadolinium / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D057927:Hydrophobic and Hydrophilic Interactions; D007074:Immunoglobulin G / Q000097:blood; D007075:Immunoglobulin M / Q000097:blood; D007668:Kidney / Q000378:metabolism; D008081:Liposomes; D008099:Liver / Q000378:metabolism; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008823:Micelles; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D013154:Spleen / Q000378:metabolism
chemical_list: D007074:Immunoglobulin G; D007075:Immunoglobulin M; D008081:Liposomes; D008823:Micelles; D011092:Polyethylene Glycols; D005682:Gadolinium