MR-guided focused ultrasound increases antibody delivery to nonenhancing high-grade glioma

Caterina Brighi; Lee Reid; Alison L White; Laura A Genovesi; Marija Kojic; Amanda Millar; Zara Bruce; Bryan W Day; Stephen Rose; Andrew K Whittaker; Simon Puttick

doi:10.1093/noajnl/vdaa030

MR-guided focused ultrasound increases antibody delivery to nonenhancing high-grade glioma

Neurooncol Adv. 2020 Mar 5;2(1):vdaa030. doi: 10.1093/noajnl/vdaa030. eCollection 2020 Jan-Dec.

Authors

Caterina Brighi^{1

2}, Lee Reid³, Alison L White^{1

2}, Laura A Genovesi⁴, Marija Kojic⁴, Amanda Millar⁴, Zara Bruce⁵, Bryan W Day^{5

6

7}, Stephen Rose³, Andrew K Whittaker^{1

2}, Simon Puttick³

Affiliations

¹ Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, Australia.
² ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, The University of Queensland, Brisbane, Australia.
³ Commonwealth Scientific and Industrial Research Organization, Australian e-Health Research Centre, Royal Brisbane and Women's Hospital, Brisbane, Australia.
⁴ Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia.
⁵ Department of Cell and Molecular Biology, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
⁶ School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, Australia.
⁷ School of Biomedical Sciences, The University of Queensland, Brisbane, Australia.

Abstract

Background: High-grade glioma (HGG) remains a recalcitrant clinical problem despite many decades of research. A major challenge in improving prognosis is the inability of current therapeutic strategies to address a clinically significant burden of infiltrating tumor cells that extend beyond the margins of the primary tumor mass. Such cells cannot be surgically excised nor efficiently targeted by radiation therapy. Therapeutic targeting of this tumor cell population is significantly hampered by the presence of an intact blood-brain barrier (BBB). In this study, we performed a preclinical investigation of the efficiency of MR-guided Focused Ultrasound (FUS) to temporarily disrupt the BBB to allow selective delivery of a tumor-targeting antibody to infiltrating tumor.

Methods: Structural MRI, dynamic-contrast enhancement MRI, and histology were used to fully characterize the MR-enhancing properties of a patient-derived xenograft (PDX) orthotopic mouse model of HGG and to develop a reproducible, robust model of nonenhancing HGG. PET-CT imaging techniques were then used to evaluate the efficacy of FUS to increase ⁸⁹Zr-radiolabeled antibody concentration in nonenhancing HGG regions and adjacent non-targeted tumor tissue.

Results: The PDX mouse model of HGG has a significant tumor burden lying behind an intact BBB. Increased antibody uptake in nonenhancing tumor regions is directly proportional to the FUS-targeted volume. FUS locally increased antibody uptake in FUS-targeted regions of the tumor with an intact BBB, while leaving untargeted regions unaffected.

Conclusions: FUS exposure successfully allowed temporary BBB disruption, localized to specifically targeted, nonenhancing, infiltrating tumor regions and delivery of a systemically administered antibody was significantly increased.

Keywords: MRI; blood; brain barrier; focused ultrasound; high-grade glioma; vasculature permeability.