Folic acid-functionalized PLGA-cystamine nanoparticles for glutathione-responsive capecitabine delivery in pancreatic cancer: in vitro and in vivo evaluation

Due to high systemic toxicity associated with conventional chemotherapy and limited drug accumulation at the tumor site, pancreatic cancer is still challenging to eliminate. To improve the intracellular transport of capecitabine, a glutathione-responsive nanocarrier system based on poly(lactic-co-glycolic acid) (PLGA) was designed. PLGA coupled with cystamine was used to create the nanoformulation, which introduced disulfide bonds that are stable in extracellular environments but cleaved in a reductive intracellular environment enriched with glutathione. This redox-sensitive mechanism enables rapid drug release specifically within cancer cells. The nanoparticle surface was functionalized with folic acid to promote folate receptor–mediated endocytosis, which is often overexpressed on pancreatic cancer, thereby further enhancing cellular uptake. DLS and TEM Microscopy confirmed a consistent nanoparticle size of FoA-PLGA-Cys-CAP 261.3 ± 2.8 nm with uniform shape, indicating suitability for therapeutic delivery. In vitro cytotoxicity studies showed an IC50 value of 77.52 ± 1.33 μg/mL and increased reactive oxygen species generation in treated cells. For in vivo evaluation, PANC1 cells were subcutaneously implanted to establish a pancreatic tumor model. Over 12 days, tumor size increased from 20.617 mm2 to 57.71 mm2. Following 10 days of treatment with the nanoformulation, tumor size significantly decreased from 57.71 mm2 to 43.099 mm2, demonstrating promising therapeutic efficacy.