Theranostics 2020; 10(4):1948-1959. doi:10.7150/thno.41161 This issue

Research Paper

Multimodal and multiscale optical imaging of nanomedicine delivery across the blood-brain barrier upon sonopermeation

Jan-Niklas May1#, Susanne K. Golombek1#, Maike Baues1, Anshuman Dasgupta1, Natascha Drude1, Anne Rix1, Dirk Rommel2, Saskia von Stillfried3, Lia Appold1, Robert Pola4, Michal Pechar4, Louis van Bloois5, Gert Storm5, Alexander J. C. Kuehne2,6, Felix Gremse1, Benjamin Theek1,7, Fabian Kiessling1,7, Twan Lammers1,5,8✉

1. Institute for Experimental Molecular Imaging (ExMI), University Clinic and Helmholtz Institute for Biomedical Engineering, RWTH Aachen University, Aachen, Germany
2. DWI - Leibniz Institute for Interactive Materials, RWTH Aachen University, Aachen, Germany
3. Institute of Pathology, University Clinic RWTH Aachen, Aachen, Germany
4. Czech Academy of Sciences, Institute of Macromolecular Chemistry, Prague, Czech Republic
5. Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands
6. Institute of Organic and Macromolecular Chemistry, Ulm University, Ulm, Germany
7. Fraunhofer MEVIS, Institute for Medical Image Computing, Aachen, Germany
8. Department of Targeted Therapeutics, University of Twente, Enschede, The Netherlands
# These authors contributed equally.

This is an open access article distributed under the terms of the Creative Commons Attribution License ( See for full terms and conditions.
May JN, Golombek SK, Baues M, Dasgupta A, Drude N, Rix A, Rommel D, von Stillfried S, Appold L, Pola R, Pechar M, van Bloois L, Storm G, Kuehne AJC, Gremse F, Theek B, Kiessling F, Lammers T. Multimodal and multiscale optical imaging of nanomedicine delivery across the blood-brain barrier upon sonopermeation. Theranostics 2020; 10(4):1948-1959. doi:10.7150/thno.41161. Available from

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Graphic abstract

Rationale: The blood-brain barrier (BBB) is a major obstacle for drug delivery to the brain. Sonopermeation, which relies on the combination of ultrasound and microbubbles, has emerged as a powerful tool to permeate the BBB, enabling the extravasation of drugs and drug delivery systems (DDS) to and into the central nervous system (CNS). When aiming to improve the treatment of high medical need brain disorders, it is important to systematically study nanomedicine translocation across the sonopermeated BBB. To this end, we here employed multimodal and multiscale optical imaging to investigate the impact of DDS size on brain accumulation, extravasation and penetration upon sonopermeation.

Methods: Two prototypic DDS, i.e. 10 nm-sized pHPMA polymers and 100 nm-sized PEGylated liposomes, were labeled with fluorophores and intravenously injected in healthy CD-1 nude mice. Upon sonopermeation, computed tomography-fluorescence molecular tomography, fluorescence reflectance imaging, fluorescence microscopy, confocal microscopy and stimulated emission depletion nanoscopy were used to study the effect of DDS size on their translocation across the BBB.

Results: Sonopermeation treatment enabled safe and efficient opening of the BBB, which was confirmed by staining extravasated endogenous IgG. No micro-hemorrhages, edema and necrosis were detected in H&E stainings. Multimodal and multiscale optical imaging showed that sonopermeation promoted the accumulation of nanocarriers in mouse brains, and that 10 nm-sized polymeric DDS accumulated more strongly and penetrated deeper into the brain than 100 nm-sized liposomes.

Conclusions: BBB opening via sonopermeation enables safe and efficient delivery of nanomedicine formulations to and into the brain. When looking at accumulation and penetration (and when neglecting issues such as drug loading capacity and therapeutic efficacy) smaller-sized DDS are found to be more suitable for drug delivery across the BBB than larger-sized DDS. These findings are valuable for better understanding and further developing nanomedicine-based strategies for the treatment of CNS disorders.

Keywords: Ultrasound, Microbubbles, Nanomedicine, Drug delivery, Blood-brain barrier