Computational insights into the 5-fluorouracil loading efficiency of chitosan-PLGA nanocarrier in water

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.