Development of a novel oral complex lipid emulsion containing triptolide for targeting pancreatic cancer.

Triptolide (TP), a diterpenoid triepoxide, exhibits strong anti-cancer activities, especially against pancreatic cancer, but its clinical application is limited by organ toxicity. TP was combined with diammonium glycyrrhizinate (DG), as a cytoprotective agent, in a novel oral complex lipid emulsion (TP/DG-CLE) to increase the therapeutic index of TP against pancreatic cancer. The emulsion was produced by subjecting phospholipid and active components to high shear conditions using high-pressure homogenisation resulting in droplets of essentially neutral or small positive charge and consistent size below 200 nm. Pharmacokinetic studies in Sprague Dawley rats revealed an AUC of TP following oral dosing of TP/DG-CLE that was fourfold higher than that achieved for TP/DG suspension, demonstrating significantly higher TP bioavailability and longer residence time in the bloodstream. Tissue distribution data obtained in mice demonstrated that TP/DG-CLE having a TP/DG weight ratio of 1:22.5 preferentially accumulated in the pancreas. Moreover, toxicology assays in rats provided indications of minor liver damage following daily administration of the emulsion for two weeks. Together these studies establish complex lipid emulsions containing TP and DG as a promising oral formulation for treatment of pancreatic cancer and establish a platform for developing new chemotherapeutic treatments.