Melich Romain, Desgranges Stéphane, Bussat Philippe, Contino-Pépin Christiane, Cherkaoui Samir
Bracco Suisse SA, Geneva, Switzerland 31 Route de la Galaise, 1228 Plan-les-Ouates, Switzerland.
Avignon Université, Unité Propre de Recherche et d'Innovation, Équipe Systèmes Amphiphiles bioactifs et Formulations Eco-compatibles, 84000 Avignon, France.
Int J Pharm. 2025 Jun 10;678:125680. doi: 10.1016/j.ijpharm.2025.125680. Epub 2025 May 5.
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.
相变造影剂在超声诊断中作为造影剂以及在治疗应用中作为超声空化核正越来越受到欢迎。全氟碳纳米液滴（PFC-ND）的一个主要局限性是其随时间推移相对有限的物理化学稳定性，这可能会影响其在诊断和治疗目的中的应用。在选择构成纳米液滴外壳的生物相容性表面活性剂方面已确定了一种可能克服此问题的策略。本研究使用微流控方法研究稳定的全氟碳纳米液滴的配方和特性。首先，我们展示了两类称为“F-TAC”和“DendriTAC”的生物相容性氟化表面活性剂（BFS）的结构和合成，它们稳定纳米液滴外壳，同时使用全氟戊烷作为液芯。研究了各种配方和工艺参数，包括表面活性剂类型、表面活性剂/全氟碳比例、稀释因子、流速比和储存条件，对纳米液滴的物理化学性质和声汽化行为的影响。纳米沉淀过程与微流控方法相结合已被证明是一种用于制备具有精确尺寸控制和均匀颗粒分布的PFC-ND的有效方法。正如预期的那样，表面活性剂和工艺参数的选择显著影响了纳米液滴的尺寸和稳定性。两类BFS均导致纳米液滴表现出显著的稳定性，通过添加海藻糖进一步增强，特别是在冷冻条件下。所有配方，无论其具体的外壳组成如何，都在相当的可汽化阈值下汽化。我们的研究结果突出了配方参数和工艺设置在控制这些纳米结构特性方面的重要性。总之，本研究为潜在生物医学应用的全氟碳纳米液滴的配方和优化提供了有价值的见解。
