Coarse-Grained Molecular Dynamics Simulations of Paclitaxel-Loaded Polymeric Micelles

Abstract

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.

Unravel the Tangle: Atomistic Insight into Ultrahigh Curcumin‐Loaded Polymer Micelles

“…[ 90 ] Micelle surface exposure of CUR atoms was analyzed via the cone algorithm [ 45 ] which was previously also used for paclitaxel‐loaded micelles. [ 91 ] A cosine value of the angle of the cone of 0.5 and a cone slant height of 0.5 nm was used. Subsequently, the amount of CUR atoms on the surface and the fractions of atoms of the micelle surface belonging to drug molecules were calculated.…”

Exploiting Pharma 4.0 Technologies in the Non-Biological Complex Drugs Manufacturing: Innovations and Implications

“…This increased drug release was attributed to the solvation of the hydrophobic core, promoting micellar swelling and reducing hydrophobic interactions, ultimately leading to a loosely packed micellar structure. In general, the computational predictions provided valuable insights into the micelle self-assembly process, morphological changes, drug release, and thermodynamic instability and showed excellent agreement with experimental results, underscoring its efficacy in studying the impact of material attributes and process parameters on the polymeric micelle formulation during continuous processing [87].…”

Effect of solvent on the emulsion and morphology of polyfluorene films: all-atom molecular dynamics approach

“…, coarse-grained (CG) MD simulation is mostly used. 55–57 Fig. 1 shows the schematic view of the emulsion system and displays the molecular structures of the emulsion components.…”

“…For investigating the morphology of emulsion systems, mesoscale modeling, i.e., coarse-grained (CG) MD simulation is mostly used. [55][56][57] Fig. 1 shows the schematic view of the emulsion system and displays the molecular structures of the emulsion components.…”