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A Tripeptide-Stabilized Nanoemulsion of Oleic Acid
Published on: February 27, 2019
Development of a novel oral complex lipid emulsion containing triptolide for targeting pancreatic cancer
Liangyu Mu1, Peiyao Wu2,3, Ying Zhang4
1Department of Pharmaceutics, School of Chinese Medicines, Shenyang Pharmaceutical University, Shenyang, PR China.
Abstract:
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(0-8 h) 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.
Insights
This study developed a novel oral complex lipid emulsion (TP/DG-CLE) combining triptolide (TP) and diammonium glycyrrhizinate (DG) to enhance pancreatic cancer treatment. The new formulation significantly improved TP bioavailability and pancreatic accumulation, showing promise for improved therapeutic outcomes.
Area of Science:
- Pharmacology
- Drug Delivery
- Oncology
Background:
- Triptolide (TP) shows potent anti-cancer effects, particularly against pancreatic cancer.
- Clinical use of TP is restricted due to significant organ toxicity.
- Diammonium glycyrrhizinate (DG) acts as a cytoprotective agent to mitigate TP's toxicity.
Purpose of the Study:
- To develop and evaluate a novel oral complex lipid emulsion (TP/DG-CLE) for enhanced pancreatic cancer therapy.
- To improve the therapeutic index of triptolide by combining it with diammonium glycyrrhizinate in an advanced drug delivery system.
- To assess the pharmacokinetics, biodistribution, and preliminary toxicology of the TP/DG-CLE formulation.
Main Methods:
- Complex lipid emulsions (CLE) were prepared using high-pressure homogenization of phospholipids and active components (TP and DG).
- Pharmacokinetic studies were conducted in Sprague Dawley rats to evaluate TP bioavailability and residence time.
- Tissue distribution in mice was analyzed to determine pancreatic accumulation of TP/DG-CLE.
- Toxicology assays in rats assessed potential organ damage following repeated administration.
Main Results:
- TP/DG-CLE demonstrated a fourfold higher area under the curve (AUC) for TP compared to TP/DG suspension, indicating significantly enhanced oral bioavailability.
- The TP/DG-CLE formulation showed preferential accumulation of TP in the pancreas in mouse models.
- Preliminary toxicology studies in rats indicated only minor liver damage after two weeks of daily administration.
Conclusions:
- Complex lipid emulsions represent a promising oral formulation for delivering triptolide and diammonium glycyrrhizinate for pancreatic cancer treatment.
- The TP/DG-CLE formulation enhances TP bioavailability and targets pancreatic tumors, potentially increasing the therapeutic index.
- This platform offers a potential strategy for developing improved chemotherapeutic treatments for pancreatic cancer.
