Key result
NC-6300 prolongs survival over epirubicin while sparing cardiac function in mice.
Why the study?
Epirubicin's antitumor effect is limited by cardiotoxicity, motivating evaluation of an epirubicin-incorporating micelle to reduce cardiotoxicity and improve efficacy.
Does NC-6300 reduce cardiotoxicity and improve antitumor effects compared to epirubicin in mice?
Does NC-6300 reduce cardiotoxicity and improve antitumor effects compared to epirubicin in mice?
NC-6300, an epirubicin-incorporating micelle, improves antitumor efficacy and prevents epirubicin-induced cardiotoxicity in preclinical models.
Supports progression of NC-6300 to human trials; leaves open clinical translation of reduced cardiotoxicity.
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.
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Takahashi et al. (2013) studied Hepatocellular carcinoma. NC-6300 vs. Epirubicin (10 mg/kg) was evaluated on Antitumor effect, survival rate, and cardiotoxicity (fractional shortening and ejection fraction). NC-6300 demonstrated a significantly potent antitumor effect and longer survival compared with epirubicin in mice, while preventing significant deteriorations in cardiac function.