Examining the Effect of Polymer Extension on Protein–Polymer Interactions That Occur during Formulation of Protein-Loaded Poly(lactic acid-co-glycolic acid)-polyethylene Glycol Nanoparticles

Abstract

Protein therapeutics have the potential to treat a wide range of ailments due to the high specificity in their function and their ability to replace missing or mutated genes that encode for key cellular processes. Despite these advantages, protein drugs alone can cause adverse effects, such as the development of cross-reactive neutralizing antibodies. Through the encapsulation of proteins into nanoparticles, adverse effects and protein degradation can be minimized, thus improving protein delivery to sites of interest in the body. Nanoparticles comprised of poly(lactic acid-co-glycolic acid)-polyethylene glycol (PLGA-PEG) diblock copolymer are promising protein delivery systems as they are well characterized, non-toxic, and biocompatible. Desirable nanoparticle characteristics, such as neutral surface charge and uniformity in size and dispersity, can be achieved but often require the iterative manipulation of formulation parameters. Chain conformations in the formulation process are very important, and determining whether or not an extended or semi-collapsed polymer chain in the presence of a protein results in more favorable binding has yet to be investigated experimentally. Therefore, this work used atomistic molecular dynamics to examine the role of polymer extension on protein binding and its impact on the encapsulation process within PLGA-PEG nanoparticles. Three polymers (PLGA-PEG, PLGA, and PEG) were evaluated and iduronate-2-sulphatase (ID2S) was used as a model protein. We found highly expanded PLGA-PEG conformations led to more favorable binding with ID2S. Furthermore, PEG oligomers were observed to undergo transient binding with ID2S that was generally less favorable when compared to the other polymer types. The results also suggest that the relaxation times of the PLGA homopolymer and the PLGA-PEG copolymer at different molecular weights in relevant solvent mediums should be considered.