In Silico and In Vitro Analysis of pH-Responsive SLS Delivery via CeBTC-Modified CNT Nanocarriers: Molecular Dynamic Simulation to Experimental Assessment

This study integrates silico multiscale modeling─including quantum mechanical (QM) and molecular dynamics (MD) simulations─with experimental in vitro validation to comprehensively evaluate the pH-responsive drug delivery behavior of CeBTC-functionalized carbon nanotube (CNT) nanocarriers for sodium lignosulfonate (SLS). Among pristine (PCNT), moderately functionalized (MFCNT), and densely functionalized CNTs (DFCNT), the 20S-5CeBTC-DFCNT system emerged as the most efficient platform. Density functional theory (DFT) analysis revealed low HOMO-LUMO gaps (SLS: 0.206 eV; CeO₂: 0.231 eV), supporting electronic reactivity and interaction compatibility. MD simulations demonstrated superior conformational stability for DFCNT with RMSD = 3.51 ± 0.33 Å, <i>R</i>_g = 16.28 ± 0.14 Å, RMSF = 1.17 ± 0.85 Å, and maximal solvent exposure (SASA = 9367.73 ± 182.07 Ų; PSA = 4147.67 ± 145.04 Ų). Drug loading interaction energy peaked at 5668.23 ± 54 kcal/mol, with Coulombic contribution of 3851.53 ± 53.36 kcal/mol. Upon pH 5.0-triggered protonation, drug (SLS) release energy reached 23616.87 ± 125 kcal/mol and the center-of-mass separation between SLS and carrier increased to 43.22 ± 6.32 Å, indicating efficient release. Notably, in vitro assays along with FE-SEM, HR-TEM, and FTIR confirmed 88% drug loading and 87.5% release over 100 h under acidic conditions, aligning closely with simulation results (100% loading, 95% release). In contrast, other nanocarriers (MFCNT and PCNT) showed lower performance, with higher RMSD (>25 Å), reduced PSA (<2200 Ų), weaker interaction energies (<4300 kcal/mol), and incomplete drug displacement (<31 Å). The release kinetics of DFCNT followed the Korsmeyer-Peppas model at pH 5.0 (<i>R</i>² = 0.98193), confirming its pH-sensitive behavior. These findings establish DFCNT as a stable, tunable, and efficient nanocarrier for targeted drug delivery in acidic pathological environments, with promising potential for future redox-responsive and combination therapies.