Abstract LB-11: Reduced cardiotoxicity and improved antitumor effect of the epirubicin-incorporating micelle NC-6300 in a hepatocellular carcinoma model

Abstract

Abstract Background: Epirubicin, an anthracycline antitumor drug, has been approved for the treatment of various human tumors. However, epirubicin has significant dose-limiting cardiotoxicity, and there are no effective therapies to prevent or reduce this cardiotoxicity. Therefore, we investigated whether the epirubicin-incorporating micelle NC-6300 was more effective than epirubicin alone in reducing cardiotoxicity and improving the antitumor effect. Method: NC-6300 comprises epirubicin covalently bound to the polyaspartate chain of the polyethylene glycol-polyaspartate block copolymer via an acid-labile hydrazone bond. The conjugate spontaneously forms a micellar structure in an aqueous milieu. The diameter of NC-6300 is 60-70 nm, and the micellar formulation is stable under physiological condition. For evaluating the antitumor effects, NC-6300 (10 or 15 mg/kg) and epirubicin (10 mg/kg) were intravenously administered once a week for 3 weeks to C57BL/6 mice bearing human hepatocellular carcinoma (HCC) Hep3B xenografts implanted subcutaneously or orthotopically (n = 6-10). Cardiotoxicity was evaluated by using echocardiography to the mice that were given NC-6300 (10 or 15 mg/kg) or epirubicin (10 mg/kg) on days 1, 8, and 15 every 4 weeks, to a total of 9 administrations for 12 weeks (n = 6 for each evaluation point). Results: Compared to epirubicin, NC-6300 showed significant antitumor activity against Hep3B. Moreover, the survival rate in the orthotopic tumor model of Hep3B was significantly higher with NC-6300 treatment than with epirubicin treatment. With respect to cardiotoxicity, epirubicin-treated mice showed significantly deteriorated fractional shortening (FS) and ejection fraction (EF) 21 days after the beginning of administration. In contrast, no mice treated with NC-6300 experienced cardiotoxicity in terms of EF or FS during the observation period. Conclusion: The findings of this study imply that NC-6300 has a strong antitumor effect against HCC. Furthermore, NC-6300 significantly reduces the cardiotoxicity of epirubicin and warrants a clinical evaluation in patients with advanced solid tumors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-11. doi:1538-7445.AM2012-LB-11