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Characterization of passive permeability after low intensity focused ultrasound mediated blood–brain barrier disruption in a preclinical model.
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- Author(s): Arsiwala, Tasneem A.; Sprowls, Samuel A.; Blethen, Kathryn E.; Fladeland, Ross A.; Wolford, Cullen P.; Kielkowski, Brooke N.; Glass, Morgan J.; Wang, Peng; Wilson, Olivia; Carpenter, Jeffrey S.; Ranjan, Manish; Finomore, Victor; Rezai, Ali; Lockman, Paul R.
- Source:
Fluids & Barriers of the CNS; 9/8/2022, Vol. 19 Issue 1, p1-11, 11p- Subject Terms:
- Source:
- Additional Information
- Subject Terms:
- Abstract: Background: Systemic drug delivery to the central nervous system is limited by presence of the blood–brain barrier (BBB). Low intensity focused ultrasound (LiFUS) is a non-invasive technique to disrupt the BBB, though there is a lack of understanding of the relationship between LiFUS parameters, such as cavitation dose, time of sonication, microbubble dose, and the time course and magnitude of BBB disruption. Discrepancies in these data arise from experimentation with modified, clinically untranslatable transducers and inconsistent parameters for sonication. In this report, we characterize microbubble and cavitation doses as LiFUS variables as they pertain to the time course and size of BBB opening with a clinical Insightec FUS system. Methods: Female Nu/Nu athymic mice were exposed to LiFUS using the ExAblate Neuro system (v7.4, Insightec, Haifa, Israel) following target verification with magnetic resonance imaging (MRI). Microbubble and cavitation doses ranged from 4–400 μL/kg, and 0.1–1.5 cavitation dose, respectively. The time course and magnitude of BBB opening was evaluated using fluorescent tracers, ranging in size from 105–10,000 Da, administered intravenously at different times pre- or post-LiFUS. Quantitative autoradiography and fluorescence microscopy were used to quantify tracer accumulation in brain. Results: We observed a microbubble and cavitation dose dependent increase in tracer uptake within brain after LiFUS. Tracer accumulation was size dependent, with 14C-AIB (100 Da) accumulating to a greater degree than larger markers (~ 625 Da–10 kDa). Our data suggest opening of the BBB via LiFUS is time dependent and biphasic. Accumulation of solutes was highest when administered prior to LiFUS mediated disruption (2–fivefold increases), but was also significantly elevated at 6 h post treatment for both 14C-AIB and Texas Red. Conclusion: The magnitude of LiFUS mediated BBB opening correlates with concentration of microbubbles, cavitation dose as well as time of tracer administration post-sonication. These data help define the window of maximal BBB opening and applicable sonication parameters on a clinically translatable and commercially available FUS system that can be used to improve passive permeability and accumulation of therapeutics targeting the brain. [ABSTRACT FROM AUTHOR]
- Abstract: Copyright of Fluids & Barriers of the CNS is the property of BioMed Central and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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