Prediction of drug-carrier interactions of PLA and PLGA drug-loaded nanoparticles by molecular dynamics simulations

terestdue to their potential as an ideal non-toxic vehicle for the delivery of active compounds in a controlled andtargeted manner. However, at the stage of academic and industrial development, the lack of regulatory instructionsfor the assessment and characterization of those nanometric materials is considerably delaying theirclinical success if compared to other macroscopic systems (i.e. microparticles). In fact, owing to their highsurface area to volume ratio, unwanted interactions between nanoparticles and biological systems may occur,leading to unexpected toxicity. In addition, knowledge of drug-polymer interactions is compulsory, as they candirectly affect many fundamental properties, such as the drug-loading ability, nanoparticle size, the drug physicalstate and stability, as well as the actual drug release profile.In this context, computational methods able to rapidly predict the binding and dynamics between drugmolecule and its carrier, and between the carrier and biological systems, are highly desirable to minimize theinvestment in drug design and development. In this study a full atomistic molecular dynamics simulationapproach was validated to investigate biomolecular behaviour of poly (lactic acid) (PLA) and poly (lactic-coglycolicacid) (PLGA) as nanoparticulate drug delivery systems. Both polymer systems have been firstly investigatedwithout drugs to better observe their tendency to interact with aqueous solution, which represents a crucial point for drug delivery systems. Subsequently, simulations were run after the incorporation of drugs. Paracetamol, Prednisolone, and Isoniazid were chosen as model drugs in relation to their different affinity with lipids. Specific interactions between polymers and drugs were considered, and a direct comparison between computational results and experimental evidences found in literature was carried out.