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Assessment of antitumor activity and acute peripheral neuropathy of 1,2-diaminocyclohexane platinum (II)-incorporating micelles (NC-4016)

Authors Ueno T, Endo K, Hori K, Ozaki N, Tsuji A, Kondo S, Wakisaka N, Murono S, Kataoka K, Kato Y, Yoshizaki T

Received 12 January 2014

Accepted for publication 15 March 2014

Published 19 June 2014 Volume 2014:9(1) Pages 3005—3012


Checked for plagiarism Yes

Review by Single-blind

Peer reviewer comments 3

Takayoshi Ueno,1 Kazuhira Endo,1 Kiyomi Hori,2 Noriyuki Ozaki,2 Akira Tsuji,1 Satoru Kondo,1 Naohiro Wakisaka,1 Shigeyuki Murono,1 Kazunori Kataoka,3,4 Yasuki Kato,5 Tomokazu Yoshizaki1

1Division of Otolaryngology-Head and Neck Surgery, 2Department of Functional Anatomy, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan; 3Department of Materials Engineering, Graduate School of Engineering, 4Division of Clinical Biotechnology, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; 5Research Division, NanoCarrier Co., Ltd, Chiba, Japan

Abstract: Oxaliplatin, a third-generation platinum compound incorporating oxalate and 
1,2-diaminocyclohexane platinum, has been widely used in chemotherapy regimens for the treatment of metastatic colorectal cancer. Because of its wide spectrum of antitumor activity, oxaliplatin has been applied for the treatment of other carcinomas. However, the antitumor activity of single-agent oxaliplatin is insufficient. To increase its antitumor effects, polymeric micellar nanoparticles incorporating 1,2-diaminocyclohexane platinum (NC-4016) have been developed. The present study was designed to evaluate the efficacy of NC-4016 and its association with peripheral neuropathy, which is a primary dose-limiting factor in oxaliplatin therapy. The in vitro antitumor activity of NC-4016 was investigated using human carcinoma cell lines. To investigate the antitumor effects of NC-4016 in vivo, nude mice bearing the human carcinoma cell line KB were administered NC-4016 or oxaliplatin. The in vitro growth-inhibiting effect of NC-4016 was significantly weaker than that of oxaliplatin. However, the antitumor efficacy of NC-4016 was superior to that of oxaliplatin in vivo. Moreover, we compared the severity of peripheral neuropathy induced by oxaliplatin and NC-4016 in a rat model. ­Oxaliplatin, NC-4016, or 5% glucose (control) were administered by a single tail vein injection. In the oxaliplatin-treated rats, neither mechanical nor heat allodynia was observed during the experimental period, whereas cold hyperalgesia/allodynia was observed from day 1 to 7. Conversely, cold hyperalgesia/allodynia was not observed in the NC-4016-treated rats. The present study demonstrated that the antitumor efficacy of NC-4016 was superior to that of oxaliplatin in a mouse model of human carcinoma cell line KB. In addition, NC-4016-treated rats did not develop acute cold hypersensitivity, which is frequently experienced by patients after oxaliplatin administration.

Keywords: oxaliplatin, carcinoma, chemotherapy, drug delivery system

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