Mixing versus Polymer Chemistry in the Synthesis of Loaded Polymer Nanoparticles through Nanoprecipitation
Résumé
Polymer nanoparticles (NPs) loaded with drugs and/or contrast-agents have become key tools in the advancement of nanomedicine, requiring robust technologies for their synthesis. Nanoprecipitation is a particularly interesting technique for the assembly of loaded polymer NPs, which is well known to proceed under kinetic control, with a strong influence of assembly conditions. On the other hand, the nature of the used polymer also influences the outcome of nanoprecipitation. Here, we investigated systematically the relative effects of mixing of the organic and aqueous phases and polymer chemistry on the formation of polymer nanocarriers. For this, two mixing schemes, manual mixing and microfluidic mixing using an impact-jet micromixer, were first evaluated, showing, respectively, mixing times of several tens of milliseconds and a few milliseconds. Copolymers of ethyl methacrylate with charged and hydrophilic groups and different polyesters (PLGA, PLA) were combined with a fluorescent dye salt and tested for particle assembly using this "slow" and "fast" mixing. Our results showed that in case of the most hydrophobic polymers the speed of mixing had no significant influence on the size and loading of the formed NPs. In contrast, in the case of less hydrophobic polymers, faster mixing led to smaller sized NPs with better encapsulation. The switch between mixing and polymer controlled assembly was directly correlated to the solubility limit of the polymers in acetonitrile-water mixtures, with a critical point for solubility limits between 15 and 20 vol% water. Our results provide simple guidelines on how to evaluate the possible influence of polymer chemistry and mixing on formation of loaded NPs, opening the way to fine tuning their properties and optimizing their large scale production.
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