title: NC-6300, an epirubicin-incorporating micelle, extends the antitumor effect and reduces the cardiotoxicity of epirubicin.
abstract: Epirubicin is widely used to treat various human tumors. However, it is difficult to achieve a sufficient antitumor effect because of dosage limitation to prevent cardiotoxicity. We hypothesized that epirubicin-incorporating micelle would reduce cardiotoxicity and improve the antitumor effect. NC-6300 comprises epirubicin covalently bound to PEG polyaspartate block copolymer through an acid-labile hydrazone bond. The conjugate forms a micellar structure of 40-80 nm in diameter in an aqueous milieu. NC-6300 (10, 15 mg/kg) and epirubicin (10 mg/kg) were given i.v. three times to mice bearing s.c. or liver xenograft of human hepatocellular carcinoma Hep3B cells. Cardiotoxicity was evaluated by echocardiography in C57BL/6 mice that were given NC-6300 (10 mg/kg) or epirubicin (10 mg/kg) in nine doses over 12 weeks. NC-6300 showed a significantly potent antitumor effect against Hep3B s.c. tumors compared with epirubicin. Moreover, NC-6300 also produced a significantly longer survival rate than epirubicin against the liver orthotopic tumor of Hep3B. With respect to cardiotoxicity, epirubicin-treated mice showed significant deteriorations in fractional shortening and ejection fraction. In contrast, cardiac functions of NC-6300 treated mice were no less well maintained than in control mice. This study warrants a clinical evaluation of NC-6300 in patients with hepatocellular carcinoma or other cancers.
authors.affiliation: Division of Developmental Therapeutics, Research Center for Innovative Oncology, Kashiwa, Japan.
authors.forename: Amane
authors.initials: A
authors.lastname: Takahashi
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Yamamoto
authors.forename: Masahiro
authors.initials: M
authors.lastname: Yasunaga
authors.forename: Yoshikatsu
authors.initials: Y
authors.lastname: Koga
authors.forename: Jun-ichiro
authors.initials: J
authors.lastname: Kuroda
authors.forename: Misato
authors.initials: M
authors.lastname: Takigahira
authors.forename: Mitsunori
authors.initials: M
authors.lastname: Harada
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Saito
authors.forename: Tatsuyuki
authors.initials: T
authors.lastname: Hayashi
authors.forename: Yasuki
authors.initials: Y
authors.lastname: Kato
authors.forename: Taira
authors.initials: T
authors.lastname: Kinoshita
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Ohkohchi
authors.forename: Ichinosuke
authors.initials: I
authors.lastname: Hyodo
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Matsumura
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects* / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy; D045744:Cell Line, Tumor; D015251:Epirubicin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology; D005260:Female; D006321:Heart / Q000187:drug effects*; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D008823:Micelles; D011506:Proteins / Q000009:adverse effects* / Q000494:pharmacology*; D011897:Random Allocation; D014018:Tissue Distribution / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D008823:Micelles; C555062:NC 6300; D011506:Proteins; D015251:Epirubicin