Niclosamide-Loaded Polyanhydride Nanoparticles to Combat Gemcitabine Resistance in Pancreatic Cancer.

PURPOSE: Pancreatic cancer (PC) is a highly lethal malignancy and lacks effective treatments. Current chemotherapies, including gemcitabine (Gem) in combination treatment regimens, produce dose-limiting toxicity, drug resistance, and ultimately limited improvement in the overall survival of PC patients. Niclosamide (Nic), a clinically safe FDA-approved anthelmintic drug has been shown to have anti-cancer properties; however, its limited bioavailability makes Nic largely ineffective as a therapeutic agent. To address this challenge, we have developed a novel combination therapy of Gem with the repurposed drug, Nic, loaded in biodegradable polyanhydride nanoparticles (NicNp), as an effective treatment option for PC. METHODS: We synthesized and characterized NicNp in vitro and evaluated their biodistribution and efficacy in xenograft and syngeneic pancreatic tumor models in mice. RESULTS: The biodistribution study indicated that NicNp accumulated in high concentrations in the pancreatic tumors of the mice with C(max) of 138 ± 74.1 µg Nic/g tissue. NicNp treatment, in combination with Gem, worked synergistically to reduce the dose of gemcitabine required to kill pancreatic cancer cells in vitro, two-fold. Additionally, the pancreatic tumor burden in the mouse models was significantly reduced, while survival was significantly increased when mice bearing pancreatic tumors were treated with the combination of NicNp and Gem. CONCLUSIONS: This study demonstrates the potential for effective repurposing Nic via nanoformulations in combination with Gem to improve PC treatment efficacy. LAY SUMMARY: Pancreatic cancer (PC) ranks among the most lethal types of cancer, with largely ineffective current treatments and toxic side effects in patients. Niclosamide is an FDA-approved anti-parasitic drug with minimal side effects, that has shown some anti-cancer properties. However, it is not effectively absorbed in the body. We produced polymer nanoparticles to deliver niclosamide effectively to treat pancreatic tumors in mice in combination with the chemotherapeutic gemcitabine. This combination treatment led to PC tumor reduction and increased the survival, demonstrating that niclosamide encapsulated in nanoparticles in combination with gemcitabine has the potential to be a more effective treatment for PC. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40883-025-00394-0.