Breaking Through the Limits: Nanomedicine at the Service of New Drug Combinations to Tackle Pancreatic Cancer

Pancreatic ductal adenocarcinoma (PDAC) is among the most aggressive cancers, with a poor prognosis due to late diagnosis and resistance to chemotherapy. Gemcitabine (GEM) monotherapy was the gold standard treatment for PDAC until the early 2010s, when two combinatorial therapies, FOLFIRINOX and GEM combined with Nab-paclitaxel, showed the benefits of the multi-drug approach and became the reference treatments for PDAC. Despite their undisputed efficacy, the overall survival of treated PDAC patients is very low, reaching approximately 12% at 5 years, and the side effects of these therapeutic protocols remain severe and not tolerated by all patients. Recent advances in understanding PDAC biology have led to new therapeutic strategies, including new drug combinations and nanomedicine. This review summarizes background information about past and present PDAC therapeutic regimens with their benefits and the drawbacks including the appearance of treatment resistance and focuses on two potential strategies to counteract the limitations of the actual therapies. First, we highlight the interest of combining disulfiram, a repurposed anti-alcoholism drug, with GEM, based on evidence of synergism between the two molecules. We then emphasize the use of drug delivery nanosystems for their ability to improve drug stability, targeting and to potentially overcome resistance and reduce side effects. Finally, we discuss the combination of multi-drug therapies and nanomedicine through the design of apposite drug delivery nanocarriers capable of encapsulating more than one drug and ensuring sustained release. This all-in-one approach should be promising for more effective therapies of this challenging disease.