Format

Send to

Choose Destination
Ultrasound Med Biol. 2020 Jan;46(1):122-136. doi: 10.1016/j.ultrasmedbio.2019.08.024. Epub 2019 Oct 2.

Distribution and Diffusion of Macromolecule Delivery to the Brain via Focused Ultrasound using Magnetic Resonance and Multispectral Fluorescence Imaging.

Author information

1
Department of Biomedical Engineering, University of Arizona, Tucson, Arizona, USA.
2
Department of Biomedical Engineering, University of Arizona, Tucson, Arizona, USA; Department of Medical Imaging, University of Arizona, Tucson, Arizona, USA.
3
Department of Pediatrics, University of Arizona, Tucson, Arizona, USA; BIO5 Research Institute, University of Arizona, Tucson, Arizona, USA.
4
Department of Biomedical Engineering, University of Arizona, Tucson, Arizona, USA; Department of Medical Imaging, University of Arizona, Tucson, Arizona, USA; BIO5 Research Institute, University of Arizona, Tucson, Arizona, USA; Evelyn F. McKnight Brain Institute, University of Arizona, Tucson, Arizona, USA. Electronic address: trouard@email.arizona.edu.

Abstract

Focused ultrasound (FUS), in combination with microbubble contrast agents, can be used to transiently open the blood-brain barrier (BBB) to allow intravascular agents to cross into the brain. Often, FUS is carried out in conjunction with magnetic resonance imaging (MRI) to evaluate BBB opening to gadolinium-based MRI contrast agents. Although MRI allows direct visualization of the distribution of gadolinium-based contrast agents in the brain parenchyma, it does not allow measurements of the distribution of other molecules crossing the BBB. Therapeutic molecules (e.g., monoclonal antibodies) are much different in size than MRI contrast agents and have been found to have different distributions in the brain after FUS-mediated BBB opening. In the work described here, we combined in vivo MRI and ex vivo multispectral fluorescence imaging to compare the distributions of MRI contrast and dextran molecules of different molecular weights (3, 70 and 500 kDa) after FUS-mediated BBB opening through a range of ultrasound pressures (0.18-0.46 MPa) in laboratory mice. The volume of brain exposed was calculated from the MRI and fluorescence images and was significantly dependent on both molecular weight and ultrasound pressure. Diffusion coefficients of the different-molecular-weight dextran molecules in the brain parenchyma were also calculated from the fluorescence images and were negatively correlated with the molecular weight of the dextran molecules. The results of this work build on a body of knowledge that is critically important for the FUS technique to be used in clinical delivery of therapeutics to the brain.

KEYWORDS:

Blood–brain barrier; Drug delivery; Focused ultrasound; Magnetic resonance imaging; Mice; Microbubbles

PMID:
31585767
PMCID:
PMC6937597
[Available on 2021-01-01]
DOI:
10.1016/j.ultrasmedbio.2019.08.024

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center