Tumor-targeted Butein-loaded PLGA nanoparticles improve gemcitabine sensitivity and prolong survival in pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal cancers, marked by late-stage diagnosis, a dense stromal microenvironment, and the rapid emergence of chemoresistance. Gemcitabine (Gem) monotherapy offers limited survival benefits, highlighting the urgent need for novel therapeutic approaches. We developed tumor-targeted Butein-loaded PLGA nanoparticles (TP-PLGA-B) to enhance drug delivery and evaluate their synergistic effects with Gem in PDAC models. Nanoparticles were characterized by size, stability, and drug release profiles. Biological efficacy was assessed through in vitro cytotoxicity, migration, colony formation assays, and in vivo therapeutic studies in a syngeneic orthotopic PDAC mouse model. TP-PLGA-B nanoparticles (∼170 nm) demonstrated pH-sensitive drug release and selective tumor targeting. Combination therapy with TP-PLGA-B and low-dose Gem significantly reduced the IC 50 by 2.5–6.2-fold compared with controls and was more synergistic than free drug combinations, inhibited EGFR, cMET, and p-STAT3 pathways, and suppressed pro-inflammatory cytokine expression. In vivo , this combination markedly decreased tumor volume, enhanced apoptosis, and extended median survival from 24 to 56 days without noticeable toxicity. Our findings support TP-PLGA-B nanoparticles as a promising strategy to enhance Gem sensitivity, reduce chemoresistance, and improve therapeutic outcomes in PDAC.