• Mintz, Akiva
• Jan, Chia-Ing
• Tazhibi, Masih
• Zhang, Xu
• Carrion, Andrea Webster
• Berg, Xander
• Mcquillan, Nicholas
• Wei, Hong-Jian
• Gallitto, Matthew
• Bendau, Ethan
• Kokossis, Danae
• Syed, Hasan R.
• Gartrell, Robyn D.
• Pavisic, Jovana
• Fonseca, Adriana
• Konofagou, Elisa E.
• Zhang, Zhiguo
• Szalontay, Luca
• Zacharoulis, Stergios

Abstract

<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Diffuse midline glioma (DMG) is a pediatric tumor with dismal prognosis. Systemic strategies have been unsuccessful and radiotherapy (RT) remains the standard-of-care. A central impediment to treatment is the blood–brain barrier (BBB), which precludes drug delivery to the central nervous system (CNS). Focused ultrasound (FUS) with microbubbles can transiently and non-invasively disrupt the BBB to enhance drug delivery. This study aimed to determine the feasibility of brainstem FUS in combination with clinical doses of RT. We hypothesized that FUS-mediated BBB-opening (BBBO) is safe and feasible with 39 Gy RT.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>To establish a safety timeline, we administered FUS to the brainstem of non-tumor bearing mice concurrent with or adjuvant to RT; our findings were validated in a syngeneic brainstem murine model of DMG receiving repeated sonication concurrent with RT. The brainstems of male B6 (Cg)-Tyrc-2J/J albino mice were intracranially injected with mouse DMG cells (PDGFB<jats:sup>+</jats:sup>, H3.3K27M, p53<jats:sup>−/−</jats:sup>). A clinical RT dose of 39 Gy in 13 fractions (39 Gy/13fx) was delivered using the Small Animal Radiation Research Platform (SARRP) or XRAD-320 irradiator. FUS was administered via a 0.5 MHz transducer, with BBBO and tumor volume monitored by magnetic resonance imaging (MRI).</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>FUS-mediated BBBO did not affect cardiorespiratory rate, motor function, or tissue integrity in non-tumor bearing mice receiving RT. Tumor-bearing mice tolerated repeated brainstem BBBO concurrent with RT. 39 Gy/13fx offered local control, though disease progression occurred 3–4 weeks post-RT.</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>Repeated FUS-mediated BBBO is safe and feasible concurrent with RT. In our syngeneic DMG murine model, progression occurs, serving as an ideal model for future combination testing with RT and FUS-mediated drug delivery.</jats:p></jats:sec>

Topics

• impedance spectroscopy
• size-exclusion chromatography