Predicting the adsorption behavior of olaparib on zinc oxide nanoparticles for improved pH-responsive drug delivery: experimental and DFT insights

The development of efficient drug delivery systems for hydrophobic anticancer drugs like Olaparib (OLA) remains a critical challenge in cancer therapy. This study presents a comprehensive investigation of OLA-loaded zinc oxide nanoparticles (OLA@ZnO) through integrated experimental and computational approaches to optimize pH-responsive drug delivery. ZnO nanoparticles were synthesized via a sol-gel method and characterized using SEM, XRD, FTIR, and UV–Vis spectroscopy, revealing successful OLA loading through Zn²⁺-carbonyl coordination and π-stacking interactions. The nanocomposites exhibited excellent colloidal stability (zeta potential = 11 mV at pH 7.4) and pH-triggered drug release, with 100 % release in 20 h (physiological pH) versus 90 % in 24 h (acidic pH). Korsmeyer-Peppas modeling confirmed diffusion-dominated release (n = 0.52) at neutral pH and erosion-controlled release (n = 0.69) in acidic conditions. Density functional theory (DFT) calculations revealed strong charge transfer, evidenced by a narrowed HOMO-LUMO gap (4.89 → 3.21 eV) and increased dipole moment (5.7 → 9.13 D). Molecular descriptors highlighted enhanced reactivity (softness = 0.621 eV⁻¹) and pH sensitivity (electrophilicity = 4.54 eV), while reduced density gradient (RDG) analysis visualized key binding interactions (−0.9 eV for Zn²⁺-C = O coordination). Thermodynamic analysis demonstrated spontaneous adsorption (ΔG = −0.77 to −0.89 eV) with exothermic behavior (ΔH = −0.87 to −1.00 eV) and entropy-driven release (ΔS = −0.00034 to −0.00037 eV/K). Size-dependent trends showed that smaller nanoparticles (0.9 nm) enabled rapid release (τ = 1.05 s) for acute therapy, while larger nanoparticles (2.0 nm) provided sustained delivery (τ = 152 s) for chronic treatment. These findings establish a robust structure-property relationship for designing tunable ZnO-based nanocarriers, offering a promising strategy to improve the therapeutic efficacy of OLA and other hydrophobic drugs in targeted cancer therapy.