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A continuous manufacturing technology based on coaxial turbulent jet in coflow was previously developed to produce paclitaxel-loaded polymeric micelles. Herein, coarse-grained molecular dynamics (CG-MD) simulations were implemented to better understand the effect of the material attributes (i.e., the drug−polymer ratio and the ethanol concentration) and process parameters (i.e., temperature) on the self-assembly process of polymeric micelles as well as to provide molecular details on micelle instability. An all-atom (AA) poly (ethylene glycol)-poly (lactic acid) (PEG−PLA) polymer model was developed as the reference for parameterizing a coarse-grained (CG) model, and the AA polymer model was further validated with experimental glass transition temperature (T g ). The model transferability was verified by comparing structural properties between the AA and CG models. The CG model was further validated with experimental data, including micelle particle size measurements and drug encapsulation efficiency. Furthermore, the encapsulation of paclitaxel into the polymeric micelles was included in the simulations, taking into consideration the interactions between the paclitaxel and the polymers. The results from various points of view demonstrated a strong dependence of the shape of the micelles on the drug encapsulation, with micelles transitioning from spherical to ellipsoidal structures with an increasing paclitaxel amount. Simulation data were also used to identify the critical aggregation number (i.e., the number of polymer and drug molecules required for transition from one shape to another). Improved micellar structural stability was found with a larger micellar size and less solvent accessibility. Lastly, an evaluation was performed on the micellar dissociation free energy using a steered molecular dynamics simulation over a range of temperatures and ethanol concentrations. These simulations revealed that at higher ethanol and temperature conditions, micelles become destabilized, resulting in greater paclitaxel release. The increased drug release was determined to originate from the solvation of the hydrophobic core, which promoted micellar swelling and an associated reduction in hydrophobic interactions, leading to a loosely packed micellar structure.

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Synthetic polymers are made of small structural units (monomers) that are connected by covalent bonds and have been used extensively in technology and everyday life. Thus, characterizing their structural and dynamical properties at the molecular level is essential to design new materials and understand their roles in a variety of application. However, systematic generation of synthetic polymer structures is challenging because there are great variations in arrangement of monomers and linkage methods (i.e., branching and tacticity of monomers). In this study, to facilitate the generation of all-atom and corresponding coarse-grained structures of various polymer structures, we present the development and case studies of Synthetic Polymer Builder in CHARMM-GUI (http://www.charmm-gui.org), a web-based interface to facilitate a building of complex simulation systems.