Distinctive Formation of PEG-Lipid Nanopatches onto Solid Polymer Surfaces Interfacing Solvents from Atomistic Simulation

Abstract

The interface between solid poly­(lactic acid-co-glycolic acid), PLGA, and solvents is described by large-scale atomistic simulations for water, ethyl acetate, and the mixture of them at ambient conditions. Interactions at the interface are dominated by Coulomb forces for water and become overwhelmingly dispersive for the other two solvents. This effect drives a neat liquid-phase separation of the mixed solvent, with ethyl acetate covering the PLGA surface and water being segregated away from it. We explore with all-atom Molecular Dynamics the formation of macromolecular assemblies on the surface of the PLGA-solvent interface when DSPE-PEG, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-(polyethylene glycol) n amine, is added to the solvent. By following in time the deposition of the DSPE-PEG macromolecules onto the PLGA surface, the mechanism of how nanopatches remain adsorbed to the surface despite the presence of the solvent is probed. These patches have a droplet-like aspect when formed at the PLGA-water interface that flatten in the PLGA-ethyl acetate interface case. Dispersive forces are dominant for the nanopatch adhesion to the surface, while electrostatic forces are dominant for keeping the solvent around the new formations. Considering the droplet-like patches as wetting the PLGA surface, we predict an effective wetting behavior at the water interface that fades significantly at the ethyl acetate interface. The predicted mechanism of PEG-lipid nanopatch formation may be generally applicable for tailoring the synthesis of asymmetric PLGA nanoparticles for specific drug delivery conditions.

Workflow for Investigating Thermodynamic, Structural, and Energy Properties of Condensed Polymer Systems

“…Part of this workflow was already successfully applied for analyzing the effects of solvents on the structure of solvated PLGA 5 . Currently, we have extended the workflow use for the analysis of PLGA(50:50) with a variety of molecular weights 13 and in nanocomposite systems 14 .…”

Forecasting molecular dynamics energetics of polymers in solution from supervised machine learning

“…Ethyl acetate (EA), C 4 H 8 O 2 , is a non-polar organic solvent commonly used for the fabrication of nanoparticles. 26,46,47 Both EA and DSPE-PEG were modeled using the all-atom generalized Amber force eld (GAFF) 48,49 with our custom-calculated restrained electrostatic potential(RESP) atomic charges, 37,39,40 which was combined with the compatible Amber-Lipid17 (ref. 50) force eld for the DSPE portion of the polymer-lipid macromolecule.…”

“…Automated energetics estimates will also be instrumental in taking decisions for concatenating independently run MD simulations 34 or ML generated stochastic trajectories with static, underlying, Boltzmann's distribution. 35,36 Our recent MD predictions 37 have conrmed that aggregates of four DSPE-PEG(2000) (lipid-polymer) macromolecules, self-assemble in water giving rise to premicellar formations. While investigating a substance solubility, researchers have been able to formulate intelligently based on the key insight that solvents, polymers, or solid matter are well characterized by solubility parameters derived from their cohesive energy density.…”