DFT investigation of 5-fluorouracil tautomerism and non-covalent interactions with PLGA nanoparticles for enhanced drug delivery and sensing.

This study investigates the non-covalent interactions between both the free and tautomeric forms of 5-fluorouracil (5-FU) and poly(lactic-co-glycolic acid) (PLGA) nanoparticles through density functional dispersion correction (DFT-D) at the B3LYP-D level in a dichloromethane (DCM) and water environments. Our results indicate that the non-covalent interactions formed between the carbonyl and amide groups of the free form of 5-FU and the carboxyl group of PLGA facilitate a rapid initial release of the drug, aligning with experimental findings. The calculated binding energies for 5-FU in its keto-enol (-0.80 eV) and di-enol forms (-0.74 eV) demonstrate exothermic processes, highlighting the enhanced drug loading capacity of the tautomeric forms compared to the free form (-0.627 eV). NBO analysis indicates a charge transfer of 0.061e in the keto-enol form, compared to 0.053e in the free form. Infrared (IR) spectra show shifts in the N-H and CO stretching frequencies, suggesting the formation of hydrogen bonds between 5-FU and the carbonyl groups of PLGA. Time-dependent DFT calculations revealed significant shifts in the optical properties of 5-FU upon interaction with the PLGA carrier. Adsorption of 5-FU in its most stable configuration resulted in a red shift to 253.56 nm, while the PLGA carrier exhibited a blue shift to 213.08 nm. Analysis of oscillator strengths indicated an increased adsorption intensity for the keto-enol form of 5-FU, suggesting a hypochromic effect. Total density of states (TDOS) analysis demonstrates that 5-FU notably influences the HOMO and LUMO levels, with PLGA nanoparticles exhibiting higher sensitivity (state I: 30.07 %) to 5-FU in one state compared to another (state VII: 28.99 %), likely due to variations in energy gaps. These findings indicate that PLGA nanoparticles possess significant potential as both drug carriers and sensors for 5-FU detection in solvent phases.