A bufadienolide-loaded submicron emulsion for oral administration: stability, antitumor efficacy and toxicity.

The purpose of this study was to develop an alternative submicron emulsion containing three bufadienolides for oral administration and evaluate its preclinical stability, efficacy, and toxicity. The bufadienolide-loaded oral submicron emulsion (BU-OE) was prepared by high-pressure homogenization. The storage stability, in vitro cytotoxicity, in vivo antitumor efficacy, acute toxicity, and long-term toxicity of BU-OE were investigated in detail to evaluate the formulation. The stability study suggested that BU-OE was stable at room temperature and could be stored for at least 18 months at 6±2 °C. The cytotoxicity test revealed that BU-OE had marked cytotoxic activities against cancer cells, but no evident inhibitory effects on normal cells. Likewise, BU-OE exhibited significant antitumor efficacy against Hep G2, HCT-8, and EC9706 cell lines and a slight inhibitory effect on BGC 803 cell line in nude mice, while comparable antitumor activity with fluorouracil injection. The LD50 of BU-OE in mice was 29.4 mg/kg (male) and 22.8 mg/kg (female), respectively. As for the long-term toxicity, BU-OE showed no apparent toxic effects except minor cardiotoxic effects which were reversible. In conclusion, submicron emulsion is a suitable delivery system for oral administration of bufadienolides, with satisfactory stability, superior antitumor efficacy and low toxicity.