Work

Niclosamide nanoparticles enhance pancreatic cancer sensitivity to gemcitabine via HIF-1α inhibition

Year: 2025

Type: article

Abstract: Pancreatic cancer (PC) is characterized by profound metabolic adaptations that support tumor progression, survival, and therapy resistance. A key regulator of these processes is hypoxia-inducible factor-1α (HIF-1α), which promotes metabolic reprogramming and chemoresistance. Since mitochondrial metabolites, such as 2-ketoglutarate modulate HIF-1α stability, disrupting mitochondrial metabolism presents a compelling therapeutic strategy for PC treatment. Niclosamide (Nic), a clinically approved anthelmintic that effectively impairs mitochondrial function and metabolic activity but suffers from poor bioavailability, limiting its clinical use. To address this limitation, we developed polyanhydride-based Nic nanoparticles (NicNps) to enhance Nic’s bioavailability and therapeutic efficacy. NicNps were characterized and evaluated in PC cell models and orthotopic gemcitabine (Gem)-resistant mouse tumor models. NicNps significantly impeded growth, disrupted mitochondrial function, suppressed metabolic activity, and downregulated HIF-1α expression, leading to a marked reduction in PC cell survival. Notably, the combination of NicNps with Gem overcame therapy resistance by impairing metabolism, synergistically reducing tumor growth, hypoxic zones, and HIF-1α-driven metabolic reprogramming. These findings underscore the potential of NicNps as a mitochondria-targeting metabolic therapy, preserving Nic’s ability to disrupt tumor metabolism while enhancing its bioavailability. By targeting hypoxia-driven metabolic adaptations, NicNps, in combination with Gem, offer a promising nanoparticle-based strategy to overcome therapy resistance and improve treatment outcomes in pancreatic cancer patients.

Source: iScience

DOI: 10.1016/j.isci.2025.114088