title: Suppression in mice of immunosurveillance against PEGylated liposomes by encapsulated doxorubicin.
abstract: PEGylated liposomes (PEG-lip) can escape from recognition by immune system and show a longer half-life in the blood than non-PEGylated liposomes. In this study, we investigated the influence of injected PEG-lip encapsulating doxorubicin (PEG-lip-DOX) on the biodistribution of subsequently injected PEG-lip in mice. PEG-lip-DOX, free doxorubicin or empty PEG-lip were initially injected into BALB/c mice via a tail vein, and 3days later [(3)H]-labeled PEG-lip ([(3)H] PEG-lip) were injected into these same mice. At 24h after the injection, the distribution of [(3)H] PEG-lip in the liver and spleen was significantly reduced in the PEG-lip-DOX group compared with that in the free doxorubicin or PEG-lip group. Consequently, the plasma concentration of [(3)H] PEG-lip was significantly elevated by the pretreatment with PEG-lip-DOX. Altered pharmacokinetics was observed at least until 72h after the injection of [(3)H] PEG-lip. The influence of the injected PEG-lip-DOX on the pharmacokinetics of the subsequently injected [(3)H] PEG-lip was clearly observed from 1 to 14days, and slightly observed on days 21 and 28, after the injection of the PEG-lip-DOX. Flow cytometric analysis showed that the number of liver Kupffer cells was significantly reduced after the treatment with PEG-lip-DOX. On the other hand, a similar alteration in the distribution of the subsequently injected [(3)H] PEG-lip was observed in immunodeficient mice such as BALB/c nu/nu and severe combined immunodeficiency (SCID) mice. These findings suggest that immune cells including liver Kupffer cells responsible for recognizing PEG-lip were selectively damaged by the encapsulated doxorubicin in PEG-lip injected initially, which damage led to prolongation of the half-life of subsequently injected [(3)H] PEG-lip in the blood.
authors.affiliation: Department of Medical Biochemistry, University of Shizuoka School of Pharmaceutical Sciences, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan; Natural Products Research Section, Research Division, National Cancer Institute Thailand, 268/1 Rama 6, Rajthavee, Bangkok 10400, Thailand.
authors.forename: Jantana
authors.initials: J
authors.lastname: Yahuafai
authors.affiliation: Department of Medical Biochemistry, University of Shizuoka School of Pharmaceutical Sciences, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Asai
authors.affiliation: Department of Medical Biochemistry, University of Shizuoka School of Pharmaceutical Sciences, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan.
authors.forename: Genki
authors.initials: G
authors.lastname: Nakamura
authors.affiliation: Department of Medical Biochemistry, University of Shizuoka School of Pharmaceutical Sciences, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Fukuta
authors.affiliation: Natural Products Research Section, Research Division, National Cancer Institute Thailand, 268/1 Rama 6, Rajthavee, Bangkok 10400, Thailand.
authors.forename: Pongpun
authors.initials: P
authors.lastname: Siripong
authors.affiliation: Global Formulation Research, Pharmaceutical Science & Technology Core Function Unit, Eisai Product Creation Systems, Eisai Co. Ltd., 5-1-3 Tokodai, Tsukuba 300-2635, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Hyodo
authors.affiliation: Global Formulation Research, Pharmaceutical Science & Technology Core Function Unit, Eisai Product Creation Systems, Eisai Co. Ltd., 5-1-3 Tokodai, Tsukuba 300-2635, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ishihara
authors.affiliation: Global Formulation Research, Pharmaceutical Science & Technology Core Function Unit, Eisai Product Creation Systems, Eisai Co. Ltd., 5-1-3 Tokodai, Tsukuba 300-2635, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kikuchi
authors.affiliation: Department of Medical Biochemistry, University of Shizuoka School of Pharmaceutical Sciences, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan. Electronic address: oku@u-shizuoka-ken.ac.jp.
authors.forename: Naoto
authors.initials: N
authors.lastname: Oku
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000494:pharmacology*; D004317:Doxorubicin / Q000008:administration & dosage / Q000494:pharmacology*; D007728:Kupffer Cells / Q000187:drug effects* / Q000276:immunology; D008081:Liposomes / Q000276:immunology* / Q000493:pharmacokinetics; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D015166:Monitoring, Immunologic; D011092:Polyethylene Glycols / Q000378:metabolism* / Q000493:pharmacokinetics
chemical_list: D000903:Antibiotics, Antineoplastic; D008081:Liposomes; D011092:Polyethylene Glycols; D004317:Doxorubicin
keywords: Biodistribution; Doxorubicin; Immunosurveillance; PEGylated liposomes; Repetitive administration