Mixing versus Polymer Chemistry in the Synthesis of Loaded Polymer Nanoparticles through Nanoprecipitation

Abstract

Polymer nanoparticles (NPs) loaded with drugs and 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 the 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 mixing times of several tens of milliseconds and a few milliseconds, respectively. Copolymers of ethyl methacrylate with charged and hydrophilic groups and different polyesters (poly(D-L-lactide-co-glycolide) and poly(lactic acid)) were combined with a fluorescent dye salt and tested for particle assembly using these "slow" and "fast" mixing methods. Our results showed that in the 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 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 % of water. Our results provide simple guidelines on how to evaluate the possible influence of polymer chemistry and mixing on the formation of loaded NPs, opening the way to fine-tune their properties and optimize their large-scale production.

Synthesis of polymeric nanoparticles by double emulsion and pH-driven: encapsulation of antibiotics and natural products for combating Escherichia coli infections

“…During the evaporation process, the polymer molecules organize themselves to generate nanoscale structures. This conventional method has become relevant due to its characteristics, such as low cost, high EE%, lower complexity, and practicality (Pulingam et al 2022 ; Combes et al 2023 ). However, it is necessary to develop and understand new methodologies with the same effectiveness, lower cost, practicality, easy reproducibility, scalable, and environmentally sustainable (Combes et al 2023 ).…”

“…This conventional method has become relevant due to its characteristics, such as low cost, high EE%, lower complexity, and practicality (Pulingam et al 2022 ; Combes et al 2023 ). However, it is necessary to develop and understand new methodologies with the same effectiveness, lower cost, practicality, easy reproducibility, scalable, and environmentally sustainable (Combes et al 2023 ). Therefore, the selection of the most appropriate methodology will require a thorough analysis considering not only the requirements of the final product but also the applicability, bioavailability, routes of administration, specific targets, and the nature of the drugs and their hydrophilicity and hydrophobicity (Panigrahi et al 2021 ).…”