title: Effect of combined treatment with the epirubicin-incorporating micelles (NC-6300) and 1,2-diaminocyclohexane platinum (II)-incorporating micelles (NC-4016) on a human gastric cancer model.
abstract: Anticancer agent-incorporating polymeric micelles accumulate effectively in tumors via the enhanced permeability and retention effect to exert potent antitumor effects. However, combined use of such micelles has not been elucidated. We compared the effect of combining the epirubicin-incorporating micelle NC-6300 and 1,2-diaminocyclohexane platinum (II) (oxaliplatin parent complex)-incorporating micelle NC-4016 (NCs) with that of epirubicin and oxaliplatin (E/O) in 44As3Luc cells using the combination index method. The in vivo antitumor activities of NCs and E/O were evaluated in mice bearing 44As3Luc xenografts. Pharmacokinetic analysis was performed by high-performance liquid chromatography and mass spectrometry. Cardiotoxicity of NC-6300 and epirubicin was assessed by echocardiography. Neurotoxicity of NC-4016 and oxaliplatin was evaluated by examining the paw withdrawal response to noxious mechanical stimuli. NCs showed a highly synergistic activity equivalent to E/O. In vivo, NCs exhibited higher antitumor activity in the subcutaneous tumor model and longer overall survival in the orthotopic tumor model than E/O (p < 0.001, p = 0.015, respectively). The intratumor concentrations of epirubicin and platinum were significantly higher following NCs than following E/O administration. Moreover, the micelles showed lower cardiotoxicity and neurotoxicity than the corresponding conventional drugs. The combined use of the micelles was associated with remarkable efficacy and favorable toxicities in the human gastric cancer model, and warrants the conduct of clinical trials.
authors.affiliation: Division of Developmental Therapeutics, Research Center for Innovative Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan; Department of Gastroenterology and Hepatology, Institute of Clinical Medicine, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Yamamoto
authors.forename: Ichinosuke
authors.initials: I
authors.lastname: Hyodo
authors.forename: Misato
authors.initials: M
authors.lastname: Takigahira
authors.forename: Yoshikatsu
authors.initials: Y
authors.lastname: Koga
authors.forename: Masahiro
authors.initials: M
authors.lastname: Yasunaga
authors.forename: Mitsunori
authors.initials: M
authors.lastname: Harada
authors.forename: Tatsuyuki
authors.initials: T
authors.lastname: Hayashi
authors.forename: Yasuki
authors.initials: Y
authors.lastname: Kato
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Matsumura
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D045744:Cell Line, Tumor; D064420:Drug-Related Side Effects and Adverse Reactions / Q000097:blood / Q000473:pathology; D015251:Epirubicin / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D006801:Humans; D051379:Mice; D008823:Micelles; D009944:Organoplatinum Compounds / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D000077150:Oxaliplatin; D013274:Stomach Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: D008823:Micelles; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D015251:Epirubicin
keywords: NC-4016; NC-6300; combination chemotherapy; gastric cancer; polymeric micelle