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Continuous-Flow Production of Perfluorocarbon-Loaded Polymeric Nanoparticles: From the Bench to Clinic.

  • Hoogendijk, Esmee1
  • Swider, Edyta1
  • Staal, Alexander H J1
  • White, Paul B2
  • van Riessen, N Koen1
  • Glaßer, Gunnar3
  • Lieberwirth, Ingo3
  • Musyanovych, Anna4
  • Serra, Christophe A5
  • Srinivas, Mangala1
  • Koshkina, Olga1, 3
  • 1 Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Geert Grooteplein 26/28, 6525GA Nijmegen, The Netherlands. , (Netherlands)
  • 2 Institute for Molecules and Materials, Radboud University, 6525 AJ Nijmegen, The Netherlands. , (Netherlands)
  • 3 Max Planck Institute for Polymer Research, Ackermannweg 10, 55128 Mainz, Germany. , (Germany)
  • 4 Fraunhofer IMM, Carl-Zeiss Str. 18-20, 55129 Mainz, Germany. , (Germany)
  • 5 Université de Strasbourg, CNRS, Institut Charles Sadron, 23 rue du Loess, F-67000 Strasbourg, France. , (France)
Published Article
ACS Applied Materials & Interfaces
American Chemical Society
Publication Date
Oct 21, 2020
DOI: 10.1021/acsami.0c12020
PMID: 33086007


Perfluorocarbon-loaded nanoparticles are powerful theranostic agents, which are used in the therapy of cancer and stroke and as imaging agents for ultrasound and 19F magnetic resonance imaging (MRI). Scaling up the production of perfluorocarbon-loaded nanoparticles is essential for clinical translation. However, it represents a major challenge as perfluorocarbons are hydrophobic and lipophobic. We developed a method for continuous-flow production of perfluorocarbon-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles using a modular microfluidic system, with sufficient yields for clinical use. We combined two slit interdigital micromixers with a sonication flow cell to achieve efficient mixing of three phases: liquid perfluorocarbon, PLGA in organic solvent, and aqueous surfactant solution. The production rate was at least 30 times higher than with the conventional formulation. The characteristics of nanoparticles can be adjusted by changing the flow rates and type of solvent, resulting in a high PFC loading of 20-60 wt % and radii below 200 nm. The nanoparticles are nontoxic, suitable for 19F MRI and ultrasound imaging, and can dissolve oxygen. In vivo 19F MRI with perfluoro-15-crown-5 ether-loaded nanoparticles showed similar biodistribution as nanoparticles made with the conventional method and a fast clearance from the organs. Overall, we developed a continuous, modular method for scaled-up production of perfluorocarbon-loaded nanoparticles that can be potentially adapted for the production of other multiphase systems. Thus, it will facilitate the clinical translation of theranostic agents in the future.

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