(650a) Exploring Structure and Dynamics of PLGA-Based Materials in Solvents Relevant to Nanoparticle Formulation
Methods: In this work, PLGA-PEG copolymer oligomers at different monomer lengths are simulated in three different solvents - water, acetone and DMSO - at 25oC and 1 bar using all atom MD and the general amber forcefield (GAFF). PLGA and PEG homopolymers were also simulated in the same solvents, for comparison. Using the residual electrostatic potential fitting method, partial atomic point charges for all oligomers were calculated. A three-point (TIP3P) explicit solvent model is used for the water, while acetone and DMSO partial charges are ascertained from past literature. Temperature control was achieved using the modified Berendsen Thermostat, while pressure control was achieved using the Parrinello-Rahman Barostat. Each simulation, following the packing of a single oligomer and solvent molecules into a cubic box with a pre-specified side length, first underwent an energy minimization step and two equilibration periods at constant moles, volume and temperature (NVT) then at constant moles, pressure and temperature (NPT). Polymer structure parameters, such as radius of gyration, persistence length, Kuhn length and Fluory scaling exponents are extracted to better understand rigidity, flexibility and length-independent behavior in each tested solvent. The positional bead autocorrelation is calculated to access the relaxation spectrum of each polymer type in solution. As a result, scaling relationship between the 1st relaxation time and monomer length is analyzed, along with solvent structure around the polymer using the radial distribution function.
Results: We show that PLGA-PEG oligomers in DMSO are the most rigid in good solvent conditions (Flory exponent > 0.5) and have the largest 1st relaxation times when compared to not only the acetone and water PLGA-PEG systems but also, the PLGA/solvent and PEG/solvent systems. Conformations of PLGA in water exhibited collapsed structures more frequently during simulation time, consistent with prior literature. PEG has a Flory exponent of ~0.5 in both water and acetone, proving that the MD model and forcefield that we employed can reproduce its amphiphilic nature in solution. Structural and dynamical scaling exponents extracted from all polymer/solvent systems are consistent with Rouse-Zimm theory and past simulation studies, showing that significant hydrodynamic interactions are largest for PLGA/DMSO and PLGA-PEG/DMSO systems and smallest for PLGA/water systems.
Conclusions: In this study, effects of PLGA-PEG copolymer monomer length and solvent choice on polymer structure and dynamics was characterized using atomistic MD simulations. Insights of molecular-level behavior of PLGA-based materials in common solvents is critical for their broad application in medicine. Furthermore, computational tools can aid and accelerate development of novel drugs by allowing for more precise control during nanoparticle formulation. Overall, these results can inform the choice of PLGA-PEG and solvent pair for the given application of interest and help guide the design of complex nanoscale architectures.