Molecular Dynamics Simulations of β-Cyclodextrin-Based Metal-Organic Frameworks for Targeted Delivery of Anticancer Drugs: Unveiling Adsorption Mechanisms and Optimizing Drug-Nanocarrier Interactions

Abstract

Developing nanocarrier-based drug delivery systems with enhanced selectivity and 7 efficiency is crucial for optimizing cancer treatment while minimizing systemic toxicity. 8 In this study, we employed molecular dynamics (MD) simulations to investigate the 9 adsorption behavior and interaction mechanisms of four anticancer drugs, Fludarabine 10 (FLU), Carmustine (BCNU), Methotrexate (MTX), and Mitoxantrone (MIT), onto β- 11 cyclodextrin-based metal-organic frameworks (β-CD-MOFs). The results indicate that 12 electrostatic interactions, primarily hydrogen bonding and van der Waals forces, play a 13 dominant role in drug adsorption, with FLU exhibiting the highest binding affinity (-69.25 14 kJ/mol) due to its compact molecular structure and purine ring system. In contrast, BCNU 15 displayed the weakest interaction, likely due to its lower molecular density and higher 16 solubility. Radial distribution function (RDF) analysis revealed strong host-guest 17 interactions within the β-CD-MOF framework between 1 and 2.5 nm, while mean square 18 displacement (MSD) data suggested that FLU experiences reduced mobility throughout the 19 75,000 ps simulation, indicative of enhanced stability on the nanocarrier surface. 20 Overall, the simulations provide molecular-level insight into the relative interaction and 21 mobility of the investigated drugs on the β-CD-MOF surface. These computational 22 findings provide a basis for subsequent experimental investigation of drug loading, release 23 behavior, and biocompatibility.