Microbubble Shell Stiffness Engineering Enhances Ultrasound Imaging, Drug Delivery, and Sonoporation
Abstract
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.
Article Details
Authors (31)
Roman A. Barmin
Institute for Experimental Molecular Imaging RWTH Aachen University Hospital 52074 Aachen Germany
MirJavad Moosavifar
Institute for Experimental Molecular Imaging RWTH Aachen University Hospital 52074 Aachen Germany
Elena Rama
Institute for Experimental Molecular Imaging RWTH Aachen University Hospital 52074 Aachen Germany
Julia Blöck
Institute for Experimental Molecular Imaging RWTH Aachen University Hospital 52074 Aachen Germany
Anne Rix
Institute For Experimental Molecular Imaging RWTH Aachen University Aachen Germany
Vladislav S. Petrovskii
Institute for Bioengineering of Catalonia Barcelona 08028 Spain
Rustam A. Gumerov
DWI – Leibniz Institute for Interactive Materials 52074 Aachen Germany
Jens Köhler
DWI – Leibniz Institute for Interactive Materials 52074 Aachen Germany
Michael Pohl
Céline Bastard
DWI – Leibniz Institute for Interactive Materials 52074 Aachen Germany
Stephan Rütten
Electron Microscope Facility RWTH Aachen University Hospital 52074 Aachen Germany
Laura Charlton
School of Engineering Institute for Materials and Processes University of Edinburgh Edinburgh EH9 3FB UK
Vu Ngoc Khiêm
Department of Continuum Mechanics RWTH Aachen University 52074 Aachen Germany
Fabio Domenici
Thomas Lisson
Chair for Medical Engineering Ruhr University Bochum Bochum Germany
Ekaterina Savina
Institute For Experimental Molecular Imaging RWTH Aachen University Aachen Germany
Rui Zhang
Jasmin Baier
Institute for Experimental Molecular Imaging RWTH Aachen University Hospital 52074 Aachen Germany
Susanne Koletnik
Institute for Experimental Molecular Imaging RWTH Aachen University Hospital 52074 Aachen Germany
Vasileios Koutsos
School of Engineering Institute for Materials and Processes University of Edinburgh Edinburgh EH9 3FB UK
Mikhail Itskov
Department of Continuum Mechanics RWTH Aachen University 52074 Aachen Germany
Gaio Paradossi
Georg Schmitz
Chair for Medical Engineering Ruhr University Bochum Bochum Germany
Tina Vermonden
Division of Pharmaceutics Utrecht Institute for Pharmaceutical Sciences (UIPS) Utrecht University Utrecht TB 3508 The Netherlands
Laura De Laporte
DWI‐Leibniz Institute for Interactive Materials e. V. Aachen Germany
Robert Göstl
DWI─Leibniz Institute for Interactive Materials, Forckenbeckstr. 50, 52074 Aachen, Germany
Andreas Herrmann
Institute of Technical and Macromolecular Chemistry, RWTH Aachen University, Worringerweg 2, 52074 Aachen, Germany
Igor I Potemkin
DWI – Leibniz Institute for Interactive Materials 52074 Aachen Germany
Fabian Kiessling
Institute for Experimental Molecular Imaging, Rheinisch-Westfälische Technische Hochschule Aachen University Hospital
Twan Lammers
Institute for Experimental Molecular Imaging
Roger M. Pallares
Institute for Experimental Molecular Imaging RWTH Aachen University Hospital 52074 Aachen Germany