Antitumor efficacy and cardiotoxic effect of doxorubicin-loaded mixed micelles in 4T1 murine breast cancer model. Comparative studies using Doxil® and free doxorubicin

Abstract

Abstract: Doxorubicin-loaded mixed micelles (DOX-micelles) were formulated employing TPGS and a poloxamine (Tetronic® T1107) in order to investigate their pharmaceutical application as an alternative anticancer nanotherapy. DOX-micelles presented unimodal behaviour, exhibiting average size values of 10.7 ± 0.2 nm and 10.4 ± 0.1 nm, before and after lyophilization, respectively. The in vitro cytotoxic effect of DOX-micelles was significantly higher (p < 0.05) than Doxil® on 4T1 murine breast cancer cells. The in vitro cell-based internalization assays showed a significant augment (p < 0.05) of the intracellular DOX content for the DOX-micelles in comparison to the liposomes and free DOX in these 4T1 cells at 2 and 6 h. Besides, DOX-micelles presented higher in vivo anticancer effect than Doxil® and equivalent potency to the free drug. Moreover, the in vivo histopathological toxicity studies revealed that the DOX-micelles produced significant less cardiac damage than free DOX, while the in vivo immunohistochemical assays exhibited a significantly higher DNA damage in the cardiac tissue with the free DOX than with our DOX-micelles. All these results demonstrate that our novel nanotechnological platform could successfully deliver DOX to the tumor with reduced cardiotoxicity, thus showing promising clinical potential as an anticancer drug delivery carrier.