Microbubble Shell Stiffness Engineering Enhances Ultrasound Imaging, Drug Delivery, and Sonoporation

Advanced Materials, vol. 38, pp. e07655

Abstract

Microbubbles (MB) are widely used as contrast agents for ultrasound (US) imaging and US-enhanced drug delivery. While the majority of studies utilize commercial MB formulations, increasing experimental evidence indicates that distinct MB features critically determine their diagnostic and therapeutic performance. Here, it is shown that shell stiffness engineering of poly(alkyl cyanoacrylate) (PACA) MB, via introducing monomers with varying alkyl chain lengths and glass transition temperatures, preserves a narrow size distribution ≈2-3 µm, while enhancing MB drug loading, in vitro sonoporation capability, and in vitro and in vivo acoustic responses. All-atom molecular dynamics simulations and spectroscopic experiments demonstrate that MB shell engineering increases drug diffusion rates in the shell, maximizing the loading capacity of the formulations. Atomic force microscopy demonstrates that the stiffness of the MB shell can be tailored by more than ten-fold, boosting sonoporation and imaging performance. Altogether, the work provides new insights into the control of polymeric MB structure and performance via dedicated shell engineering, promoting applications in US imaging and therapy.

Authors 29

1. Roman A. Barmin Aachen Institute for Experimental Molecular Imaging

   Universitätsklinikum Aachen · RWTH Aachen University

   Affiliation as printed

   Institute for Experimental Molecular Imaging RWTH Aachen University Hospital 52074 Aachen Germany

   Institute for Experimental Molecular Imaging, RWTH Aachen University Hospital, 52074 Aachen, Germany

2. Mirjavad Moosavifar Aachen Institute for Experimental Molecular Imaging

   Universitätsklinikum Aachen · RWTH Aachen University

   Affiliation as printed

   Institute for Experimental Molecular Imaging RWTH Aachen University Hospital 52074 Aachen Germany

   Institute for Experimental Molecular Imaging, RWTH Aachen University Hospital, 52074 Aachen, Germany

3. Elena Rama Aachen Institute for Experimental Molecular Imaging

   Universitätsklinikum Aachen · RWTH Aachen University

   Affiliation as printed

   Institute for Experimental Molecular Imaging RWTH Aachen University Hospital 52074 Aachen Germany

   Institute for Experimental Molecular Imaging, RWTH Aachen University Hospital, 52074 Aachen, Germany

4. Anne Rix Aachen Institute for Experimental Molecular Imaging

   Universitätsklinikum Aachen · RWTH Aachen University

   Affiliation as printed

   Institute for Experimental Molecular Imaging RWTH Aachen University Hospital 52074 Aachen Germany

   Institute for Experimental Molecular Imaging, RWTH Aachen University Hospital, 52074 Aachen, Germany

5. Vladislav S. Petrovskii

   Institute for Bioengineering of Catalonia

   Affiliation as printed

   Institute for Bioengineering of Catalonia Barcelona 08028 Spain

   Institute for Bioengineering of Catalonia, Barcelona, 08028 Spain

6. Rustam A. Gumerov Aachen

   DWI – Leibniz Institute for Interactive Materials

   Affiliation as printed

   DWI – Leibniz Institute for Interactive Materials 52074 Aachen Germany

7. Jens Köhler Aachen

   DWI – Leibniz Institute for Interactive Materials

   Affiliation as printed

   DWI – Leibniz Institute for Interactive Materials 52074 Aachen Germany

8. Céline Bastard Aachen Department of Advanced Materials for Biomedicine Institute of Applied Medical Engineering Institute of Technical and Macromolecular Chemistry Department of Advanced Materials for Biomedicine Institute of Applied Medical Engineering

   DWI – Leibniz Institute for Interactive Materials · RWTH Aachen University

   Affiliation as printed

   DWI – Leibniz Institute for Interactive Materials 52074 Aachen Germany

   Department of Advanced Materials for Biomedicine Institute of Applied Medical Engineering RWTH Aachen University 52074 Aachen Germany

   Institute of Technical and Macromolecular Chemistry RWTH Aachen University 52074 Aachen Germany

   Department of Advanced Materials for Biomedicine, Institute of Applied Medical Engineering, RWTH Aachen University, 52074 Aachen, Germany

9. Stephan Rütten Aachen Electron Microscope Facility

   Universitätsklinikum Aachen · RWTH Aachen University

   Affiliation as printed

   Electron Microscope Facility RWTH Aachen University Hospital 52074 Aachen Germany

   Electron Microscope Facility, RWTH Aachen University Hospital, 52074 Aachen, Germany

10. Laura Charlton

    University of Edinburgh

    Affiliation as printed

    School of Engineering Institute for Materials and Processes University of Edinburgh Edinburgh EH9 3FB UK

    School of Engineering, Institute for Materials and Processes, University of Edinburgh, Edinburgh, EH9 3FB UK

11. Vu Ngoc Khiêm Aachen Department of Continuum Mechanics

    RWTH Aachen University

    Affiliation as printed

    Department of Continuum Mechanics RWTH Aachen University 52074 Aachen Germany

    Department of Continuum Mechanics, RWTH Aachen University, 52074 Aachen, Germany

12. Fabio Domenici

    University of Rome Tor Vergata

    Affiliation as printed

    Department of Chemical Science and Technologies University of Rome “Tor Vergata” Rome 00133 Italy

    Department of Chemical Science and Technologies, University of Rome "Tor Vergata", Rome, 00133 Italy

13. Thomas Lisson

    Ruhr University Bochum

    Affiliation as printed

    Chair for Medical Engineering Faculty of Electrical Engineering and Information Technology Ruhr University Bochum 44801 Bochum Germany

    Chair for Medical Engineering, Faculty of Electrical Engineering and Information Technology, Ruhr University Bochum, 44801 Bochum, Germany

14. Ekaterina Savina Aachen Institute for Experimental Molecular Imaging

    Universitätsklinikum Aachen · RWTH Aachen University

    Affiliation as printed

    Institute for Experimental Molecular Imaging RWTH Aachen University Hospital 52074 Aachen Germany

    Institute for Experimental Molecular Imaging, RWTH Aachen University Hospital, 52074 Aachen, Germany

15. Rui Zhang Aachen Institute for Experimental Molecular Imaging

    Universitätsklinikum Aachen · RWTH Aachen University

    Affiliation as printed

    Institute for Experimental Molecular Imaging RWTH Aachen University Hospital 52074 Aachen Germany

    Institute for Experimental Molecular Imaging, RWTH Aachen University Hospital, 52074 Aachen, Germany

16. Jasmin Baier Aachen Institute for Experimental Molecular Imaging

    Universitätsklinikum Aachen · RWTH Aachen University

    Affiliation as printed

    Institute for Experimental Molecular Imaging RWTH Aachen University Hospital 52074 Aachen Germany

    Institute for Experimental Molecular Imaging, RWTH Aachen University Hospital, 52074 Aachen, Germany

17. Susanne Koletnik Aachen Institute for Experimental Molecular Imaging

    Universitätsklinikum Aachen · RWTH Aachen University

    Affiliation as printed

    Institute for Experimental Molecular Imaging RWTH Aachen University Hospital 52074 Aachen Germany

    Institute for Experimental Molecular Imaging, RWTH Aachen University Hospital, 52074 Aachen, Germany

18. Vasileios Koutsos

    University of Edinburgh

    Affiliation as printed

    School of Engineering Institute for Materials and Processes University of Edinburgh Edinburgh EH9 3FB UK

    School of Engineering, Institute for Materials and Processes, University of Edinburgh, Edinburgh, EH9 3FB UK

19. Mikhail Itskov Aachen Department of Continuum Mechanics

    RWTH Aachen University

    Affiliation as printed

    Department of Continuum Mechanics RWTH Aachen University 52074 Aachen Germany

    Department of Continuum Mechanics, RWTH Aachen University, 52074 Aachen, Germany

20. Gaio Paradossi

    University of Rome Tor Vergata

    Affiliation as printed

    Department of Chemical Science and Technologies University of Rome “Tor Vergata” Rome 00133 Italy

    Department of Chemical Science and Technologies, University of Rome "Tor Vergata", Rome, 00133 Italy

21. Georg Schmitz

    Ruhr University Bochum

    Affiliation as printed

    Chair for Medical Engineering Faculty of Electrical Engineering and Information Technology Ruhr University Bochum 44801 Bochum Germany

    Chair for Medical Engineering, Faculty of Electrical Engineering and Information Technology, Ruhr University Bochum, 44801 Bochum, Germany

22. Tina Vermonden

    Utrecht University

    Affiliation as printed

    Division of Pharmaceutics Utrecht Institute for Pharmaceutical Sciences (UIPS) Utrecht University Utrecht TB 3508 The Netherlands

    Division of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Utrecht TB, 3508 The Netherlands

23. Laura De Laporte Aachen Department of Advanced Materials for Biomedicine Institute of Applied Medical Engineering Institute of Technical and Macromolecular Chemistry Department of Advanced Materials for Biomedicine Institute of Applied Medical Engineering

    DWI – Leibniz Institute for Interactive Materials · RWTH Aachen University

    Affiliation as printed

    DWI – Leibniz Institute for Interactive Materials 52074 Aachen Germany

    Department of Advanced Materials for Biomedicine Institute of Applied Medical Engineering RWTH Aachen University 52074 Aachen Germany

    Institute of Technical and Macromolecular Chemistry RWTH Aachen University 52074 Aachen Germany

    Department of Advanced Materials for Biomedicine, Institute of Applied Medical Engineering, RWTH Aachen University, 52074 Aachen, Germany

24. Robert Göstl Aachen Institute of Technical and Macromolecular Chemistry

    University of Wuppertal · DWI – Leibniz Institute for Interactive Materials · RWTH Aachen University

    Affiliation as printed

    DWI – Leibniz Institute for Interactive Materials 52074 Aachen Germany

    Department of Chemistry and Biology University of Wuppertal 42119 Wuppertal Germany

    Institute of Technical and Macromolecular Chemistry RWTH Aachen University 52074 Aachen Germany

    Institute of Technical and Macromolecular Chemistry, RWTH Aachen University, 52074 Aachen, Germany

25. Andreas Herrmann Aachen Institute of Technical and Macromolecular Chemistry

    DWI – Leibniz Institute for Interactive Materials · RWTH Aachen University

    Affiliation as printed

    DWI – Leibniz Institute for Interactive Materials 52074 Aachen Germany

    Institute of Technical and Macromolecular Chemistry RWTH Aachen University 52074 Aachen Germany

    Institute of Technical and Macromolecular Chemistry, RWTH Aachen University, 52074 Aachen, Germany

26. Igor I. Potemkin Aachen

    DWI – Leibniz Institute for Interactive Materials

    Affiliation as printed

    DWI – Leibniz Institute for Interactive Materials 52074 Aachen Germany

27. Fabian M. Kiessling Aachen Institute for Experimental Molecular Imaging

    Universitätsklinikum Aachen · RWTH Aachen University

    Affiliation as printed

    Institute for Experimental Molecular Imaging RWTH Aachen University Hospital 52074 Aachen Germany

    Institute for Experimental Molecular Imaging, RWTH Aachen University Hospital, 52074 Aachen, Germany

28. Twan Lammers corresponding Aachen Institute for Experimental Molecular Imaging

    Universitätsklinikum Aachen · RWTH Aachen University

    Affiliation as printed

    Institute for Experimental Molecular Imaging RWTH Aachen University Hospital 52074 Aachen Germany

    Institute for Experimental Molecular Imaging, RWTH Aachen University Hospital, 52074 Aachen, Germany

29. Roger M. Pallares corresponding Aachen Institute for Experimental Molecular Imaging

    Universitätsklinikum Aachen · RWTH Aachen University

    Affiliation as printed

    Institute for Experimental Molecular Imaging RWTH Aachen University Hospital 52074 Aachen Germany

    Institute for Experimental Molecular Imaging, RWTH Aachen University Hospital, 52074 Aachen, Germany