Enhancing Polymeric Microbubble Monodispersity and Acoustic Responses through Selective Reagent Sourcing

Molecular Pharmaceutics, vol. 22, pp. 7068–7075

Abstract

Gas-filled microbubbles (MBs) are widely used as contrast agents for ultrasound (US) imaging and are increasingly being explored for US-mediated drug delivery. Polymeric poly(butyl cyanoacrylate) (PBCA) MBs are particularly well-suited for these applications due to their relatively narrow size distribution, strong acoustic responsiveness, and high drug-loading capacity. While past studies have focused on enhancing the performance of MBs through polymer chemistry, the impact of reagent sourcing has received little attention. The butyl cyanoacrylate monomer, being highly reactive, is commercialized in the presence of chemicals that prevent self-polymerization. As a result, monomers from different suppliers may vary in additives and polymerization characteristics. This study demonstrates that the choice of monomer source strongly affects the size distribution, acoustic response, and payload capability of PBCA MBs. Optimized reagent selection improved the monodispersity of the samples, reducing the half-width at half-maximum of their size distributions from 30 to 16% relative to their diameters. Furthermore, differences in polymer chain length and shell thickness, driven by the monomer source, lead to 180% increases in both drug loading capacity and acoustic responsiveness. These results highlight reagent sourcing as a critical (and previously underappreciated) factor in improving the characteristics and performance of polymeric MBs.

Authors 12

1. Mirjavad Moosavifar Aachen

   Universitätsklinikum Aachen · RWTH Aachen University

   Affiliation as printed

   Institute for Experimental Molecular Imaging

   RWTH Aachen University Hospital

2. Roman A. Barmin Aachen

   Universitätsklinikum Aachen · RWTH Aachen University

   Affiliation as printed

   Institute for Experimental Molecular Imaging

   RWTH Aachen University Hospital

3. Rui Zhang Aachen

   Universitätsklinikum Aachen · RWTH Aachen University

   Affiliation as printed

   Institute for Experimental Molecular Imaging

   RWTH Aachen University Hospital

4. Céline Bastard Aachen DWI - Leibniz Institute for Interactive Materials

   DWI – Leibniz Institute for Interactive Materials · RWTH Aachen University

   Affiliation as printed

   Advanced Materials for Biomedicine, Institute of Applied Medical Engineering

   Chair for Macromolecular Materials for Medicine, Institute for Technical and Macromolecular Chemistry

   DWI − Leibniz Institute for Interactive Materials

   RWTH Aachen University

5. Jens Koehler Aachen DWI - Leibniz Institute for Interactive Materials

   DWI – Leibniz Institute for Interactive Materials

   Affiliation as printed

   DWI − Leibniz Institute for Interactive Materials

6. Stephan Rütten Aachen

   Universitätsklinikum Aachen · RWTH Aachen University

   Affiliation as printed

   Electron Microscope Facility

   RWTH Aachen University Hospital

7. Sven Thoröe‐Boveleth Aachen

   RWTH Aachen University

   Affiliation as printed

   Institute for Occupational, Social and Environmental Medicine, Medical Faculty

   RWTH Aachen University

8. Thomas Kraus Aachen

   RWTH Aachen University

   Affiliation as printed

   Institute for Occupational, Social and Environmental Medicine, Medical Faculty

   RWTH Aachen University

9. Laura De Laporte Aachen DWI - Leibniz Institute for Interactive Materials

   DWI – Leibniz Institute for Interactive Materials · RWTH Aachen University

   Affiliation as printed

   Advanced Materials for Biomedicine, Institute of Applied Medical Engineering

   Chair for Macromolecular Materials for Medicine, Institute for Technical and Macromolecular Chemistry

   DWI − Leibniz Institute for Interactive Materials

   RWTH Aachen University

10. Fabian M. Kiessling Aachen

    Universitätsklinikum Aachen · RWTH Aachen University

    Affiliation as printed

    Institute for Experimental Molecular Imaging

    RWTH Aachen University Hospital

11. Twan Lammers Aachen

    Universitätsklinikum Aachen · RWTH Aachen University

    Affiliation as printed

    Institute for Experimental Molecular Imaging

    RWTH Aachen University Hospital

12. Roger M. Pallares corresponding Aachen

    Universitätsklinikum Aachen · RWTH Aachen University

    Affiliation as printed

    Institute for Experimental Molecular Imaging

    RWTH Aachen University Hospital