Molecular-Level Insights into the Diffusion of a Hydrophobic Drug in a Disordered Block Copolymer Micelle by Molecular Dynamics Simulation

Previously, all-atom molecular dynamics (MD) simulations of a single hydrophobic drug molecule in pseudo-micelles (consisting of one polymer chain surrounded by several water molecules) were used to gain insight into drug diffusion in nano-sized micelles. Although it was shown that hydrogen bonding dominates the drug diffusivity, it was not clear to what extent a pseudo-micelle model captures the drug diffusion dynamics in a full micelle. Since drug release from a stable drug-loaded micelle occurs on very long timescales, all-atom MD simulations of the drug diffusion are prohibitively costly. To reduce the computational cost, herein, an all-atom MD simulation is performed starting from a disordered structure of a full Cucurbitacin B (CuB)-loaded poly (ethylene oxide-b-caprolactone) block copolymer micelle in water. It is found that both the CuB and water dynamics yield nonlinear sub-diffusive mean-squared displacements, which result from molecular crowding in the micelle environment and extensive hydrogen bonding interactions between the water/CuB molecules and polymer chains. Moreover, it is found that the hydrogen bonding and diffusion dynamics in the pseudo-micelle are not representative of those in the full micelle. The computational approach used herein is expected to yield molecular-level information that can aid in understanding in-vitro drug release data from nano-sized micelles.