Abstract The therapeutic application of 5-fluorouracil (5-FU) is limited by its rapid metabolism, systemic toxicity, and drug resistance, which motivates the development of efficient polymer-based nanocarriers. In this study, the non-covalent interactions between 5-FU and a chitosan-conjugated poly(lactic-co-glycolic acid) (CS–PLGA) hybrid nanocarrier were investigated using density functional theory (DFT) at the PBE-D3/6–311 + G** level in an aqueous environment modeled via the Polarizable Continuum Model (PCM). Structural analysis indicates that adsorption of 5-FU induces minor elongations in PLGA carbonyl and ester bonds (up to ~ 0.01 Å), along with slight angular distortions, suggesting weak to moderate hydrogen bonding and electrostatic interactions while preserving the structural integrity of the polymer backbone. Adsorption energies ranging from -0.87 to -1.16 eV suggest energetically favorable adsorption of 5-FU on the CS–PLGA surface. Frontier molecular orbital analysis shows a moderate reduction in the HOMO–LUMO gap upon complex formation (ΔE g ≈ 15–17%), accompanied by an increase in dipole moment, indicating enhanced polarity of the drug–carrier system. UV–Vis simulations reveal bathochromic shifts in the absorption maxima (271–295 nm), reflecting electronic perturbations induced by drug adsorption, consistent with excited-state stabilization through hydrogen bonding and local electrostatic interactions. Charge transfer, ESP, and NBO analyses indicate partial electron redistribution from CS–PLGA to 5-FU, particularly in selected configurations, consistent with non-covalent adsorption. Infrared (IR) spectral shifts further support hydrogen-bond-mediated interactions between functional groups of the drug and polymer. Therefore, the results suggest that CS–PLGA provides a stable and responsive environment for 5-FU adsorption, supporting its potential application as a nanocarrier for controlled drug delivery.
Fatima et al. (Mon,) studied this question.