Co-delivery of Quercetin and Resveratrol via Polymeric Nanoparticles for Enhanced Therapeutic Efficacy Against Colorectal Cancer

Abstract

Colorectal cancer (CRC) remains a major global health burden, emphasizing the need for targeted therapies with improved efficacy and fewer adverse effects. Quercetin and resveratrol possess substantial anticancer activity, but their therapeutic application is limited by poor bioavailability, instability, and rapid degradation. Quercetin- and resveratrol-co-loaded polymeric nanoparticles (QRNPs) were formulated using poly(lactic-co-glycolic acid) (PLGA) and D-α-tocopheryl polyethylene glycol succinate (TPGS). The optimized formulation was evaluated for particle size, zeta potential, encapsulation efficiency, morphology, drug–polymer compatibility, pH-dependent drug release, gastrointestinal stability, cellular uptake, cytotoxicity, and apoptosis in Caco-2 colorectal cancer cells. Optimized QRNPs showed a particle size of 174–177 nm, zeta potential of approximately −22 to −24 mV, and encapsulation efficiency above 80%. FTIR analysis confirmed drug–polymer compatibility, while HR-TEM revealed uniform spherical morphology. Drug-release studies demonstrated minimal release at pH 7.4 and increased release at pH 5.5, indicating preferential release under acidic tumor-like conditions. QRNPs also remained stable in simulated gastrointestinal fluids, demonstrating formulation robustness. Compared with free quercetin and resveratrol, QRNPs produced greater cytotoxicity, with CC50 values of 48.84 μg/mL at 24 h and 32.75 μg/mL at 48 h. Fluorescence imaging demonstrated enhanced cellular uptake, and Annexin V-FITC analysis confirmed increased apoptosis in treated cells. PLGA–TPGS-based quercetin–resveratrol nanoparticles improved drug stability, cellular uptake, pH-responsive release, gastrointestinal robustness, and in-vitro anticancer activity. These findings support their potential as a promising nanocarrier system for improving colorectal cancer therapy through efficient co delivery of quercetin and resveratrol, while potentially reducing limitations of free drugs.