CD44-targeted cyclodextrin-hyaluronic acid nanoparticles carrying gemcitabine and paclitaxel to pancreatic cancer.

Pancreatic cancer remains one of the fatal malignancies due to its aggressive nature, late diagnosis, and poor responsiveness to conventional chemotherapy. Overcoming drug resistance and enhancing tumor-specific drug delivery are key challenges in improving therapeutic outcomes. This study aimed to develop actively targeted cyclodextrin-based nanoparticles co-loaded with gemcitabine (GEM) and paclitaxel (PCX) to improve efficacy against pancreatic cancer, particularly in drug-resistant phenotypes. Hyaluronic acid (HA) was used to functionalize the nanoparticles for CD44-mediated active targeting. Comprehensive physicochemical characterization including particle size, zeta potential, drug loading, release profile, and stability was conducted. In vitro studies covered both 2D monolayer and 3D spheroid models of pancreatic cancer, including drug-resistant Panc-1 cells. Apoptosis induction and cholesterol depletion were assessed for mechanistic evaluation. In vivo studies in tumor-bearing mice were performed for efficacy, biodistribution, and systemic safety. All nanoparticle formulations exhibited sub-200 nm diameters, high drug loading efficiencies (>50 %), and sustained release profiles. HA-functionalized nanoparticles demonstrated enhanced cellular uptake, significant cytotoxicity, and apoptosis in both drug-sensitive and resistant cells. In vivo, CD44 targeted dual-drug nanoparticles significantly inhibited tumor growth, showed enhanced intratumoral accumulation, and exhibited no systemic toxicity. These findings suggest that HA-functionalized amphiphilic cyclodextrin nanoparticles co-loaded with GEM and PCX represent a promising strategy to overcome chemoresistance and improve therapeutic efficacy in pancreatic cancer.