Chitosan-graft-poly(2-(diethylamino)ethyl acrylamide) nanoparticles as a pH-sensitive nanocarrier: design, fabrication, physicochemical characterization, and controlled delivery of erlotinib

Abstract pH-sensitive nanoparticles offer a promising strategy to improve therapeutic outcomes while minimizing systemic toxicity. In this study, poly(2-(diethylamino)ethyl acrylamide)-grafted chitosan (CHS-g-PDEAEAm) copolymers with various compositions were synthesized via a microwave-induced method and developed as pH-responsive nanocarriers for erlotinib (ET), a hydrophobic anticancer drug. The successful grafting of PDEAEAm onto the CHS backbone was confirmed by FTIR, 1 H-NMR, and 13 C-NMR analyses. Subsequently, ET-loaded CHS-g-PDEAEAm nanoparticles (NPs) were fabricated, and their physicochemical properties, both ET-loaded and unloaded, were systematically characterized using TEM/FE-SEM, DLS, FTIR, XRD, BET, TGA, and DSC analyses. The obtained NPs exhibited high ET entrapment efficiency, satisfactory stability, and a sustained, pH-dependent drug release profile, with slower release at physiological pH and accelerated release under acidic conditions. Furthermore, ET release was influenced by the grafting percentage, and CHS-g-PDEAEAm@ET NPs displayed a slower ET release compared to CHS@ET NPs. ET release from most NPs followed Higuchi-type diffusion-controlled kinetics. In vitro cytotoxicity studies revealed good biocompatibility of CHS-g-PDEAEAm NPs toward L-929 fibroblast cells (86.89% cell viability at 200 μg/mL), while ET-loaded NPs demonstrated pronounced anticancer activity against A-549 lung cancer cells (6.24% cell viability at 200 μg/mL). Overall, the CHS-g-PDEAEAm NPs demonstrated favorable colloidal stability, pH-sensitivity, sustained drug release, good biocompatibility with low hemolytic activity, and promising anticancer activity, suggesting their potential applicability as nanocarriers for hydrophobic anticancer drugs. Graphical abstract