Acoustically responsive monodisperse nanodroplets stabilized with biocompatible fluorinated surfactants

Phase-changed contrast agents are receiving increased popularity in both ultrasound diagnostic as contrast agents, and therapeutic application as ultrasound-cavitation nuclei. A main limitation of perfluorocarbon nanodroplets (PFC-ND) is their relatively limited physicochemical stability over time, which may affect their use for diagnostic and therapy purposes. A possible strategy to overcome this issue has been identified in the selection of biocompatible surfactants constituting the nanodroplets shell. This study investigates the formulation and characterization of stable perfluorocarbon nanodroplets using a microfluidic approach. Firstly, we present the structure and synthesis of two families of biocompatible fluorinated surfactants (BFS) called "F-TAC" and "DendriTAC" stabilizing the nanodroplets shell, while perfluoropentane is used as liquid core. The influence of various formulation and process parameters, including surfactant type, surfactant/PFC ratio, dilution factor, flow rate ratio and storage conditions, on the physicochemical properties and acoustic vaporization behavior of the nanodroplets was investigated. The nanoprecipitation process combined to a microfluidic approach has proven to be a powerful approach for the preparation of PFC-NDs with precise size control and uniform particle distribution. As expected, the choice of surfactant and process parameters significantly influenced the NDs size and stability. Both classes of BFS resulted in nanodroplets exhibiting notable stability, which was further enhanced by the addition of trehalose, especially under freezing conditions. All formulations, regardless of their specific shell composition, vaporized at comparable vaporizable thresholds. Our findings highlight the importance of formulation parameters, and process settings in controlling the properties of these nanostructures. In conclusion, this study provides valuable insights into the formulation and optimization of perfluorocarbon nanodroplets for potential biomedical applications.