Nanoparticle shape improves delivery: rational coarse grain molecular dynamics (rCG-MD) of taxol in worm-like PEG-PCL micelles.

Nanoparticle shape can improve drug delivery, based in part on recent findings that flexible, worm-like nanocarriers (Worms) increase the amount of drug delivered to tumors and shrink the tumors more effectively than spherical micelles (Spheres). Here, all-atom molecular dynamics (MD) simulations are used to build a rational coarse grain (rCG) model that helps clarify shape-dependent effects in delivery of the widely used anticancer drug Taxol by block copolymer micelles. Potentials for rCG-MD were developed to examine the partitioning of this hydrophobic-aromatic drug into Worms and Spheres that self-assemble in water from poly(ethyleneglycol)-poly(caprolactone) (PEG-PCL), a weakly segregating amphiphile. PCL is a biodegradable, hydrophobic polymer widely used in biomaterials and accurately modeled here. Thermodynamic integration of the force to pull a single Taxol molecule from the micelles into solvent shows that twice as much drug loads into Worms than Spheres, fully consistent with experiments. Diffusivity of drug in the hydrated PEG corona is surprisingly slow compared to that in the core, indicative of strong but transient drug-polymer interactions. The distinctly distended corona of the Worms enhances such interactions and reflects the same balance of molecular forces that underlie an experimentally-validated phase diagram for simulated Spheres, Worms, and Bilayers. Moreover, with realistic drug loadings in micro-second simulations, Taxol is seen to draw PEG chains into the PCL core, dispersing the drug while localizing it near the interface—thus providing a molecular explanation for a measurable burst release of drug as well as the enhanced delivery seen with Worms.