Comparison of Sonication Patterns and Microbubble Administration Strategies for Focused Ultrasound-Mediated Large-Volume Drug Delivery.

Abstract

OBJECTIVE:

Diffuse intrinsic pontine glioma (DIPG) is the most common and deadliest brainstem tumor in children. Focused ultrasound combined with microbubble-mediated BBB opening (FUS-BBBO) is a promising technique for overcoming the frequently intact blood-brain barrier (BBB) in DIPG to enhance therapeutic drug delivery to the brainstem. Since DIPG is highly diffusive, large-volume FUS-BBBO is needed to cover the entire tumor region. The objective of this study was to determine the optimal treatment strategy to achieve efficient and homogeneous large-volume BBBO at the brainstem for the delivery of an immune checkpoint inhibitor, anti-PD-L1 antibody (aPD-L1).

METHODS:

Two critical parameters for large-volume FUS-BBBO, multi-point sonication pattern (interleaved vs. serial) and microbubble injection method (bolus vs. infusion), were evaluated by treating mice with four combinations of these two parameters. 2D Passive cavitation imaging (PCI) was performed for monitoring the large-volume sonication.

RESULTS:

Interleaved sonication combined with bolus injection of microbubbles resulted in 1.29 to 2.06 folds higher efficiency than other strategies as evaluated by Evans blue extravasation. The average coefficient of variation of the Evans blue delivery was 0.66 for interleaved sonication with bolus injection, compared to 0.68-0.88 for all other strategies. Similar trend was also observed in the quantified total cavitation dose and coefficient of variance of the cavitation dose. This strategy was then applied to deliver fluorescently labeled aPD-L1 which was quantified using fluorescence imaging. A strong segmented linear correlation (R2 = 0.81) was found between the total cavitation dose and the total fluorescence intensity of aPD-L1 delivered at different sonication pressures (0.15 MPa, 0.30 MPa, and 0.45 MPa).

SIGNIFICANCE:

Findings from this study suggest that efficient and homogeneous large-volume FUS-BBBO can be achieved by interleaved sonication combined with bolus injection of microbubbles, and the efficiency and homogeneity can be monitored by PCI.

• Authors: Yan Gong, Dezhuang Ye, Chih-Yen Chien, Yimei Yue, Hong Chen
• Journal: IEEE transactions on bio-medical engineering (IEEE Trans Biomed Eng) Vol. 69 Issue 11 Pg. 3449-3459 (11 2022) ISSN: 1558-2531 [Electronic] United States
• PMID: 35476579 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural)

Chemical References

• Evans Blue
• Immune Checkpoint Inhibitors

Topics

• Animals
• Mice
• Blood-Brain Barrier
• Drug Delivery Systems (methods)
• Evans Blue
• Immune Checkpoint Inhibitors
• Microbubbles
• Sonication (methods)