Association of Gemcitabine and Paclitaxel to Drug-combination Nanoparticles Leads to Long-acting Pharmacokinetics, Enhances Plasma and Pancreatic Drug Exposure Relating to Tumor Regression: Interventional Studies in an Orthotopic Pancreatic Tumor Model

Abstract

Pancreatic cancer is one of the deadliest forms of cancer for which there is no cure available. Current first-line treatment regimens of drugs have made progress in improving the overall prognosis of pancreatic cancer but are ultimately limited by systemic toxicity from off-target drug exposure due to their inability to effectively localize to the tumor. Equipped with a reliable mouse model of pancreatic cancer and a novel technology called DcNP that enables producing a combination drug product containing two disparately water-soluble gemcitabine (G) and insoluble paclitaxel (T), this thesis research has evaluated the ability of GT-in-DcNP to enhance pancreatic tumor exposure and impact tumor progression. We found that a single dose of GT-in-DcNP administered intraperitoneally (IP) can lead to prolonged tumor regression that cannot be accomplished with GT in a free soluble formulation nor with GT-in-DcNP dosed intravenously. Future investigation on the impact of multiple IP doses of GT-in-DcNP may provide a better understanding of the ability of this route, dosing frequency, and additional optimization of dosage formulation to potentially eliminate pancreatic cancer. With additional refinement, validation, and safety studies, the findings of this research may serve as a targeted drug-combination strategy for consideration of further development as a product intended for the treatment of people living with pancreatic cancer.