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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. [ABSTRACT FROM AUTHOR]

Isobaric–isothermalmolecular dynamics simulation was usedto study the diffusion of a hydrophobic drug Cucurbitacin B (CuB)in pseudomicelle environments consisting of poly(ethylene oxide-b-caprolactone) (PEO-b-PCL) swollen byvarious amounts of water. Two PEO-b-PCL configurations,linear and branched, with the same total molecular weight were used.For the branched configuration, the block copolymer contained onelinear block of PEO with the same molecular weight as that of thePEO block used in the linear configuration but with one end connectingto three PCL blocks with the same chain length, hereafter denotedPEO-b-3PCL. Regardless of the configuration, thesimulation results showed that the diffusivity of CuB was insensitiveto the water concentration up to ∼8 wt % while that of waterdecreased with an increasing water concentration. The diffusivityof CuB (10–8cm2/s) was 3 orders of magnitudelower than that of water (10–5cm2/s).This is attributed to the fact that CuB relied on the wiggling motionof the block copolymers to diffuse while water molecules diffusedvia a hopping mechanism. The rates at which CuB and water diffusedinto PEO-b-PCL were twice those in PEO-b-3PCL because the chain mobility and the degree of swelling are higherand there are fewer intermolecular hydrogen bonds in the case of PEO-b-PCL. The velocity autocorrelation functions of CuB showthat the free volume holes formed by PEO-b-3PCL aremore rigid than those formed by PEO-b-PCL, makingCuB exhibit higher-frequency collision motion in PEO-b-3PCL than in PEO-b-PCL, and the difference in frequencyis insensitive to water concentration. [ABSTRACT FROM AUTHOR]