Chemically tuned radiolabeling and membrane affinity in Drug-Functionalized carbon nanotube nanocarriers

Radiolabeled nanocarriers that can simultaneously deliver therapeutic and diagnostic agents are promising for targeted cancer therapy. In this study, we employed molecular dynamics and metadynamics simulations to investigate how the chemical identity of drug molecules influences the behavior of technetium-99 m (⁹⁹ᵐTc)-loaded carbon nanotube (CNT) nanocarriers at the atomic scale. Four clinically relevant drugs-methotrexate, diclofenac, ketotifen, and piroxicam-were conjugated to a single-walled CNT (SWCNT) via a bifunctional chelating group. Our results revealed that drug structure significantly affects radionuclide binding strength, molecular diffusion, and membrane affinity. The methotrexate-functionalized nanocarrier exhibited the most stable technetium coordination (- 825.80 kJ/mol), the lowest diffusion coefficient (0.0070 × 10⁻⁵ cm²/s), and the strongest interaction with a model phospholipid membrane (- 1376.02 kJ/mol). Free energy landscapes reconstructed from metadynamics simulations further confirmed the high thermodynamic stability of this configuration. These findings suggest that rational drug selection can effectively tune the physicochemical behavior of CNT-based radiopharmaceuticals, providing a mechanistic foundation for designing multifunctional nanocarriers with improved performance for nuclear imaging and site-specific drug delivery.