Transferrin Receptor‐Targeted Nonspherical Microbubbles for Blood–Brain Barrier Sonopermeation

Advanced Materials, vol. 35, pp. e2308150

Abstract

Microbubbles (MB) are widely used for ultrasound (US) imaging and drug delivery. MB are typically spherically shaped, due to surface tension. When heated above their glass transition temperature, polymer-based MB can be mechanically stretched to obtain an anisotropic shape, endowing them with unique features for US-mediated blood-brain barrier (BBB) permeation. It is here shown that nonspherical MB can be surface-modified with BBB-specific targeting ligands, thereby promoting binding to and sonopermeation of blood vessels in the brain. Actively targeted rod-shaped MB are generated via 1D stretching of spherical poly(butyl cyanoacrylate) MB and via subsequently functionalizing their shell with antitransferrin receptor (TfR) antibodies. Using US and optical imaging, it is demonstrated that nonspherical anti-TfR-MB bind more efficiently to BBB endothelium than spherical anti-TfR-MB, both in vitro and in vivo. BBB-associated anisotropic MB produce stronger cavitation signals and markedly enhance BBB permeation and delivery of a model drug as compared to spherical BBB-targeted MB. These findings exemplify the potential of antibody-modified nonspherical MB for targeted and triggered drug delivery to the brain.

Authors 18

1. Anshuman Dasgupta Aachen Institute for Experimental Molecular Imaging

   Harvard University · Universitätsklinikum Aachen · RWTH Aachen University

   Affiliation as printed

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

   John A. Paulson School of Engineering and Applied Sciences Harvard University Boston MA 02134 USA

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

   John A. Paulson School of Engineering and Applied Sciences, Harvard University, Boston, MA, 02134 USA

2. Tao Sun

   Brigham and Women's Hospital · Harvard University

   Affiliation as printed

   Department of Radiology Brigham and Women's Hospital Harvard Medical School Boston MA 02115 USA

   John A. Paulson School of Engineering and Applied Sciences Harvard University Boston MA 02134 USA

   Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115 USA

   John A. Paulson School of Engineering and Applied Sciences, Harvard University, Boston, MA, 02134 USA

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 Clinic 52074 Aachen Germany

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

4. Alessandro Motta Aachen Institute for Experimental Molecular Imaging

   Universitätsklinikum Aachen · RWTH Aachen University

   Affiliation as printed

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

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

5. Yongzhi Zhang

   Brigham and Women's Hospital · Harvard University

   Affiliation as printed

   Department of Radiology Brigham and Women's Hospital Harvard Medical School Boston MA 02115 USA

   Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115 USA

6. Chanikarn Power

   Brigham and Women's Hospital · Harvard University

   Affiliation as printed

   Department of Radiology Brigham and Women's Hospital Harvard Medical School Boston MA 02115 USA

   Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115 USA

7. Diana Moeckel Aachen Institute for Experimental Molecular Imaging

   Universitätsklinikum Aachen · RWTH Aachen University

   Affiliation as printed

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

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

8. Stecia-Marie P. Fletcher

   Brigham and Women's Hospital · Harvard University

   Affiliation as printed

   Department of Radiology Brigham and Women's Hospital Harvard Medical School Boston MA 02115 USA

   Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115 USA

9. Mirjavad Moosavifar Aachen Institute for Experimental Molecular Imaging

   Universitätsklinikum Aachen · RWTH Aachen University

   Affiliation as printed

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

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

10. 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 Clinic 52074 Aachen Germany

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

11. Céline Porte Aachen Institute for Experimental Molecular Imaging

    Universitätsklinikum Aachen · RWTH Aachen University

    Affiliation as printed

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

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

12. Eva Miriam Buhl Aachen Electron Microscopy Facility Institute of Pathology Electron Microscopy Facility Institute of Pathology

    RWTH Aachen University

    Affiliation as printed

    Electron Microscopy Facility Institute of Pathology RWTH Aachen University 52074 Aachen Germany

    Electron Microscopy Facility, Institute of Pathology, RWTH Aachen University, 52074 Aachen, Germany

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

    DWI – Leibniz Institute for Interactive Materials · RWTH Aachen University

    Affiliation as printed

    DWI – Leibniz Institute for Interactive Materials RWTH Aachen University Hospital 52074 Aachen Germany

14. Roger M. Pallares Aachen Institute for Experimental Molecular Imaging

    Universitätsklinikum Aachen · RWTH Aachen University

    Affiliation as printed

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

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

15. 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 Clinic 52074 Aachen Germany

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

16. Nathan Judson McDannold

    Brigham and Women's Hospital · Harvard University

    Affiliation as printed

    Department of Radiology Brigham and Women's Hospital Harvard Medical School Boston MA 02115 USA

    Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115 USA

17. Samir Mitragotri corresponding

    Harvard University

    Affiliation as printed

    John A. Paulson School of Engineering and Applied Sciences Harvard University Boston MA 02134 USA

    John A. Paulson School of Engineering and Applied Sciences, Harvard University, Boston, MA, 02134 USA

18. 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 Clinic 52074 Aachen Germany

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