Cardiac safety and antitumoral activity of a new nitric oxide derivative of pegylated epirubicin in mice

Abstract

The use of epirubicin is limited by the risk of a dilatory congestive heart failure that develops as a consequence of induction of a mitochondrial-dependent cardiomyocyte apoptosis. In a previous in-vitro study, we have provided evidence that a new formulation of pegylated epirubicin- bearing moieties that release nitric oxide, named BP-747, exerted a potent antitumoral activity against a colon cancer cell line, which was completely devoid of cytotoxic activity against cardiomyocytes. The aim of this study was to investigate the antitumoral and cardiotoxic profile of BP-747 in Caco-2 and SKOV-2 tumor-bearing mice. Epirubicin-induced cardiomyopathy was detected by clinical (survival, weight loss), anatomical (heart weight loss) and biochemical evaluations (measurement of serum troponin and creatine phosphokinase levels). The antitumoral activity was investigated by the measurement of tumor diameters and weight. In comparison with free epirubicin and pegylated epirubicin, BP-747 showed more potent antineoplastic effects, as demonstrated by the 95% reduction of tumor volume. Moreover, while administration of epirubicin and pegylated epirubicin resulted in the development of a severe anthracycline cardiomyopathy, BP-747-treated mice were virtually devoid of clinical and biochemical signs of cardiotoxicity. The present data provide evidence that addition of a nitric oxide-releasing moiety to pegylated epirubicin confers a new and unique cytotoxic profile to the drug.

Cancer Treatment-Induced Cardiotoxicity: a Cardiac Stem Cell Disease?

“…More recently a formulation of epirubicin has been produced in which a nitric oxide (NO) release moiety has been constructed [96]. Results in mice are encouraging and have indicated that by this approach the anti-neoplastic activity of anthracycline is increased in the presence of significant cardioprotection.…”

Combination Drug Delivery Approaches in Metastatic Breast Cancer

“…While unmodified PEG can only conjugate two drug molecules per chain (one on each end), Pasut et al developed a PEG with a dendritic structure on one end that allowed coupling of upto 8 nitric oxide (NO) and one epirubicin (EPI) molecule per chain [99, 100]. In vivo studies confirmed that the PEG-NO-EPI conjugate displayed anticancer activity but was less cardiotoxic [100, 101]. This combination is of particular interest as EPI and NO induce different pharmacological responses that are tissue-dependent.…”

Drug and protein delivery by polymer conjugation

“…The conjugate was first extensively studied in vitro; those studies found enhanced antitumor activity and reduced toxicity against cardiomyocytes and endothelial cells following the addition of a NO-releasing moiety [18,86]. When it was investigated in vivo, the conjugate demonstrated promising anticancer activity [87].…”