title: Antitumor efficacy and biodistribution of liposomal sepantronium bromide (YM155), a novel small-molecule survivin suppressant.
abstract: Sepantronium bromide (YM155) exhibits time-dependent antitumor activity, although the plasma half-life of YM155 after a bolus intravenous (i.v.) administration is very short. Therefore, greater antitumor efficacy is obtained by continuous infusion than by bolus i.v. administration. In the present study, we attempted to liposomalize YM155 to obtain a longer circulation time than that achieved by bolus i.v. administration and yet retain sufficient antitumor activity. Encapsulation of YM155 in polyethylene glycol-coated liposomes extended the half-life of the drug, and high tumor accumulation of the drug was observed. Bolus i.v. administration of liposomal YM155 by a weekly administration regimen showed antitumor activity comparable to that obtained by the continuous infusion without severe toxicity in a murine xenograft model. Therefore, this liposomal formulation can be a new dosage form of YM155 that achieves sufficient efficacy and safety and is a more convenient administration regimen for users. It should be noted that liposomal YM155 showed unexpectedly high accumulation in the kidneys. This is a specific finding for liposomal YM155, offering important information for the consideration of the potential toxicity of liposomal YM155.
authors.affiliation: Pharmaceutical Research and Technology Labs., Technology, Astellas Pharma Inc., Yaizu-shi, Japan; Department of Medical Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, Suruga-ku, Japan. Electronic address: hiroki.kawano@astellas.com.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Kawano
authors.affiliation: Pharmaceutical Research and Technology Labs., Technology, Astellas Pharma Inc., Yaizu-shi, Japan; Department of Medical Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, Suruga-ku, Japan.
authors.forename: Kohsuke
authors.initials: K
authors.lastname: Shakushiro
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., Tsukuba-shi, Japan.
authors.forename: Mari
authors.initials: M
authors.lastname: Nakata
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., Tsukuba-shi, Japan.
authors.forename: Aya
authors.initials: A
authors.lastname: Kita
authors.affiliation: Pharmaceutical Research and Technology Labs., Technology, Astellas Pharma Inc., Yaizu-shi, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Maeda
authors.affiliation: Pharmaceutical Research and Technology Labs., Technology, Astellas Pharma Inc., Yaizu-shi, Japan.
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Watanabe
authors.affiliation: Pharmaceutical Research and Technology Labs., Technology, Astellas Pharma Inc., Yaizu-shi, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Sako
authors.affiliation: Department of Medical Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, Suruga-ku, Japan.
authors.forename: Naoto
authors.initials: N
authors.lastname: Oku
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D019540:Area Under Curve; D045744:Cell Line, Tumor; D004578:Electron Spin Resonance Spectroscopy; D006801:Humans; D007093:Imidazoles / Q000737:chemistry* / Q000493:pharmacokinetics; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D007668:Kidney / Q000187:drug effects; D008081:Liposomes / Q000737:chemistry; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009285:Naphthoquinones / Q000737:chemistry* / Q000493:pharmacokinetics; D011092:Polyethylene Glycols / Q000737:chemistry; D011471:Prostatic Neoplasms / Q000188:drug therapy; D012097:Repressor Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D000077022:Survivin; D014018:Tissue Distribution; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C117749:Birc5 protein, mouse; D007093:Imidazoles; D051034:Inhibitor of Apoptosis Proteins; D008081:Liposomes; D009285:Naphthoquinones; D012097:Repressor Proteins; D000077022:Survivin; D011092:Polyethylene Glycols; C523798:sepantronium
keywords: Antitumor efficacy; Biodistribution; Kidney accumulation; Liposome; Pharmacokinetics; Sepantronium bromide (YM155)