Varying PLGA and Peg Oligomer Extension Reveals Favorable Protein/Polymer Interactions Critical to Drug Loading of PLGA-Peg Nanoparticles
Protein therapeutics have the potential to treat a wide range of life-threatening diseases in affected patient populations. When compared to small molecule drugs, this class of macromolecules can provide high specificity and complexity in their function and replace critical proteins in individuals missing necessary genes or have mutated genes containing key structure and function information. Despite these advantages, protein drugs can cause adverse effects, depending on the route of administration. Such effects include protease recognition and cleavage once in the bloodstream, development of cross-reactive neutralizing antibodies and an increased risk of injection-site or viral infections. Polymer nanoparticles can better ensure translation of these therapeutics to the clinic by protecting them against degradation and immune recognition, controlling their release, assist in crossing biological barriers and by targeting specific sites of action. Nanoparticles (NPs) comprised of polylactic-co-glycolic acid polyethylene glycol (PLGA-PEG) are non-toxic, non-immunogenic. Using this diblock copolymer, desirable nanoparticle characteristics, such as neutral surface charge and uniformity in size and dispersity, can be achieved but only after extensive manipulation of formulation parameters. Moreover, experimental investigations of molecular-level behavior during nanoparticle synthesis are few, due to detection limits and/or lack of instrument sensitivity. Therefore, this work uses restrained, atomistic molecular dynamics (MD) to examine the role of polymer extension in the protein encapsulation process within PLGA-PEG NPs. We simulated three PLGA (N = 20 monomer length) and three PEG (N = 20 monomer length) polymer oligomers in the presence of a model protein, bovine serum albumin, and an explicit water solvent medium. A harmonic potential was used to restrain the oligomersâ radius of gyration (Rg) at various values reflecting different levels of extension arising from varying solvent quality. Results indicate that protein-polymer contacts are promoted at intermediate values of polymer Rg for both PLGA and PEG.