Focused ultrasound-mediated blood–brain barrier opening is safe and feasible with moderately hypofractionated radiotherapy for brainstem diffuse midline glioma
Background 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. Methods 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^{+} $, H3.3K27M, $ p53^{−/−} $). 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). Results 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. Conclusion 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..
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:22 |
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| Enthalten in: |
Journal of translational medicine - 22(2024), 1 vom: 30. März |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Tazhibi, Masih [VerfasserIn] |
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| Links: |
Volltext [kostenfrei] |
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| Themen: |
Blood–brain barrier opening |
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| Anmerkungen: |
© The Author(s) 2024 |
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| doi: |
10.1186/s12967-024-05096-9 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
SPR055358837 |
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| 520 | |a Background 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. Methods 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^{+} $, H3.3K27M, $ p53^{−/−} $). 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). Results 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. Conclusion 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. | ||
| 650 | 4 | |a Focused ultrasound |7 (dpeaa)DE-He213 | |
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| 700 | 1 | |a McQuillan, Nicholas |4 aut | |
| 700 | 1 | |a Wei, Hong-Jian |4 aut | |
| 700 | 1 | |a Gallitto, Matthew |4 aut | |
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| 700 | 1 | |a Webster Carrion, Andrea |4 aut | |
| 700 | 1 | |a Berg, Xander |4 aut | |
| 700 | 1 | |a Kokossis, Danae |4 aut | |
| 700 | 1 | |a Zhang, Xu |4 aut | |
| 700 | 1 | |a Zhang, Zhiguo |4 aut | |
| 700 | 1 | |a Jan, Chia-Ing |4 aut | |
| 700 | 1 | |a Mintz, Akiva |4 aut | |
| 700 | 1 | |a Gartrell, Robyn D. |4 aut | |
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| 700 | 1 | |a Fonseca, Adriana |4 aut | |
| 700 | 1 | |a Pavisic, Jovana |4 aut | |
| 700 | 1 | |a Szalontay, Luca |4 aut | |
| 700 | 1 | |a Konofagou, Elisa E. |4 aut | |
| 700 | 1 | |a Zacharoulis, Stergios |4 aut | |
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