Effect of solvent composition on self-assembly behavior of tryptophan-based supramolecular gel loading doxorubicin using molecular dynamic simulation

<p indent="0mm">Injectable peptide-based hydrogels have garnered significant attention for their capacity to directly deliver active drug molecules to tumor lesions, enabling long-term and sustained release. The interaction modes and intensities between the active drug and the gelators are crucial factors influencing macroscopic properties of the gel, such as mechanical properties and the sustained release of the drugs. The delicate balance of solvent-solute interactions plays a significant role between the molecular structure and solvent composition. This article employs all-atom molecular dynamics (AA MD) simulations to investigate the self-assembled structures and intermolecular interactions between the anticancer drug doxorubicin (DOX) and the tryptophan-based amphipathic supramolecular gel NH₂-Gly-CONH-Trp-CONH-C₁₀ (GTC₁₀, Gly=Glycine, Trp=Tryptophan, C₁₀=decylamine) in five distinct dimethyl sulfoxide (DMSO)/H₂O solvent environments. When the simulation reaches equilibrium after <sc>200 ns,</sc> the different solvent environments significantly affect the fiber self-assembly structure. In the 10% DMSO solvent, column-shaped fibers were observed, with DOX distributed within the fibers and co-assembling with GTC₁₀. However, as the DMSO proportion in the solvent increases, the self-assembled structure transitions from columnar fibers to aggregated micelles, and DOX molecules shift from the fiber interior to the periphery. Upon increasing the DMSO ratio to 50%, DOX is ultimately distributed between the micelles formed by the gelator GTC₁₀. Quantitative analyses of the solvent accessible surface area (SASA), intermolecular electrostatic interaction energy, van der Waals interaction energy, and hydrogen bond distribution revealed that stronger van der Waals contributions in low-DMSO-content solvents promote the formation of higher-order aggregated fibers in the DOX/GTC₁₀ system. The enhanced intermolecular interactions observed at the molecular level in low-DMSO solvents were validated by experimentally accelerated gelation kinetics, while the fiber-disruptive behaviors predicted in high-DMSO solvents aligned with the loss of thixotropic properties in corresponding experiments. These simulation results provide molecular-level insights and theoretical foundations for screening drug-loaded gels tailored to specific application scenarios.