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

Abstract

Focused ultrasound (FUS), in combination with microbubble contrast agents, can be used to transiently open the bloodÀbrain 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 (0.18À0.46 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.

Recent Advances on Ultrasound Contrast Agents for Blood-Brain Barrier Opening with Focused Ultrasound

“…FUS-induced BBB opening enhances the delivery of drugs in the central nervous system [ 9 , 10 , 11 ]. Currently, the FUS-induced delivery of several compounds is under investigation for the treatment of diseases such as glioblastoma [ 12 ], neurodegenerative diseases like Alzheimer’s [ 13 ], Parkinson’s [ 14 ], or genetic diseases [ 15 ].…”

Verification of Blood-Brain Barrier Disruption Based on the Clinical Validation Platform Using a Rat Model with Human Skull

“…The BBBD target region was the right caudate putamen (CP). This location was selected for its clinical relevance to neurological disease and to minimize the amount of tissue boundary in the FUS focal area [ 31 ]. Before sonication, the microbubbles (0.02 mL/kg, Definity, Lantheus Medical Imaging, North Billerica, MA, USA) were diluted 1:50 in normal saline and injected via a tail vein catheter using an automated syringe pump (Pump 11, Harvard Apparatus, Holliston, MA, USA) for 10 s. This was perfomed to ensure that the circulating microbubbles fully reached the target region.…”

Acoustic Holograms for Bilateral Blood-Brain Barrier Opening in a Mouse Model

“…Note that this new lens provides an enhanced efficiency for the transcranial focusing compared with the lens designed for the calibration used transcranially, as the new design includes the compensation for the aberrations of the coupling cone, skull, and brain of the animal. The output voltage of the function generator was increased accordingly to 297 mV obtaining 400 kPa-PNP to safely open the BBB [4], [5], [59], [60]. Two test mice were sonicated using these input parameters, and we detected gadolinium perfusion in T1-MRI images throughout almost the whole brain.…”