title: Hemoglobin vesicles, polyethylene glycol (PEG)ylated liposomes developed as a red blood cell substitute, do not induce the accelerated blood clearance phenomenon in mice.
abstract: The hemoglobin vesicle (HbV) is an artificial oxygen carrier encapsulating a concentrated hemoglobin solution in a liposome of which the surface is covered with polyethylene glycol (PEG). It was recently reported that repeated injections of PEGylated liposomes induce the accelerated blood clearance (ABC) phenomenon, in which serum anti-PEG IgM plays an essential role. To examine this issue, we investigated whether HbV induces the ABC phenomenon in mice at a dose of 0.1 mg Hb/kg, a dose that is generally known to induce the ABC phenomenon, or at 1400 mg Hb/kg, which is proposed for clinical use. At 7 days after the first injection of nonlabeled HbV (0.1 mg Hb/kg), the mice received HbV in which the Hb had been labeled with (125)I. After a second injection, HbV was rapidly cleared from the circulation, and uptake clearances in liver and spleen were significantly increased. In contrast, at a dose of 1400 mg Hb/kg, the pharmacokinetics of HbV was negligibly affected by repeated injection. It is interesting to note that IgM against HbV was produced 7 days postinjection at both of the above doses, and their recognition site was determined to be 1,2-distearoyl-sn-glycero-3-phosphatidylethanolamine-N-PEG in HbV. These results suggest that a clinical dose of HbV does not induce the ABC phenomenon, and that suppression of ABC phenomenon is caused by the saturation of phagocytic processing by the mononuclear phagocyte system. Thus, we conclude that induction of the ABC phenomenon would not be an issue in the dose regimen used in clinical settings.
authors.affiliation: Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Taguchi
authors.forename: Yukino
authors.initials: Y
authors.lastname: Urata
authors.forename: Makoto
authors.initials: M
authors.lastname: Anraku
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Watanabe
authors.forename: Daisuke
authors.initials: D
authors.lastname: Kadowaki
authors.forename: Hiromi
authors.initials: H
authors.lastname: Sakai
authors.forename: Hirohisa
authors.initials: H
authors.lastname: Horinouchi
authors.forename: Koichi
authors.initials: K
authors.lastname: Kobayashi
authors.forename: Eishun
authors.initials: E
authors.lastname: Tsuchida
authors.forename: Toru
authors.initials: T
authors.lastname: Maruyama
authors.forename: Masaki
authors.initials: M
authors.lastname: Otagiri
mesh_terms: D000818:Animals; D001802:Blood Substitutes / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism; D004337:Drug Carriers / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism; D004912:Erythrocytes / Q000737:chemistry / Q000378:metabolism; D006454:Hemoglobins / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008081:Liposomes; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects / Q000502:physiology; D051379:Mice; D011092:Polyethylene Glycols / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism
chemical_list: D001802:Blood Substitutes; D004337:Drug Carriers; D006454:Hemoglobins; D008081:Liposomes; D011092:Polyethylene Glycols