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[Preprint]. 2023 Apr 6:2023.04.05.534448. [Version 1] doi: 10.1101/2023.04.05.534448

MRI-Guided Focused Ultrasound Blood-Brain Barrier Opening Increases Drug Delivery and Efficacy in a Diffuse Midline Glioma Mouse Model

Payton Martinez, Genna Nault, Jenna Steiner, Michael F Wempe, Angela Pierce, Breaunna Brunt, Mathew Slade, Andrew Mongin, Jane Song, Kang-Ho Song, Nicholas Ellens, Natalie Serkova, Adam Green, Mark Borden
PMCID: PMC10104021  PMID: 37066205

Abstract

Diffuse intrinsic pontine glioma (DIPG) is the most common and deadliest pediatric brainstem tumor and is difficult to treat with chemotherapy in part due to the blood-brain barrier (BBB). Focused ultrasound (FUS) and microbubbles (MBs) have been shown to cause BBB disruption (BBBD), allowing larger chemotherapeutics to enter the parenchyma. Panobinostat is an example of a promising in vitro agent in DIPG with poor clinical efficacy due to low BBB penetrance. In this study, we hypothesized that using FUS to disrupt the BBB allows higher concentrations of panobinostat to accumulate in the tumor, providing a therapeutic effect. Mice were orthotopically injected with a patient-derived DMG cell line, BT-245. MRI was used to guide FUS/MB (1.5 MHz, 0.615 MPa PNP, 1 Hz PRF, 10 ms PL, 3 min treatment time) / (25 µL/kg, IV) targeting to the tumor location. In animals receiving panobinostat (10 mg/kg, IP) in combination with FUS/MB, a 3-fold increase in tumor panobinostat concentration was observed, with only insignificant increase of the drug in the forebrain. In mice receiving three weekly treatments, the combination of panobinostat and FUS/MB led to a 71% reduction of tumor volumes by MRI ( p = 0.01). Furthermore, FUS/MB improved the mean survival from 21 to 31 days ( p < 0.0001). Our study demonstrates that FUS-mediated BBBD can increase the delivery of panobinostat to an orthotopic DMG tumor, providing a strong therapeutic effect and increased survival.

One Sentence Summary

FUS and microbubbles can increase the delivery of panobinostat to a patient-derived xenograft (PDX) orthotopic DMG tumor, providing a strong therapeutic effect and increased survival.

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