Focused ultrasound-mediated blood-brain barrier opening is safe and feasible with moderately hypofractionated radiotherapy for brainstem diffuse midline glioma
© 2024. The Author(s)..
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 |
|---|
| Erscheinungsjahr: |
2024 |
|---|---|
| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:22 |
|---|---|
| Enthalten in: |
Journal of translational medicine - 22(2024), 1 vom: 30. März, Seite 320 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Tazhibi, Masih [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
Blood–brain barrier opening |
|---|
| Anmerkungen: |
Date Completed 01.04.2024 Date Revised 02.04.2024 published: Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1186/s12967-024-05096-9 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM37044972X |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM37044972X | ||
| 003 | DE-627 | ||
| 005 | 20240403000746.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 240331s2024 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1186/s12967-024-05096-9 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1361.xml |
| 035 | |a (DE-627)NLM37044972X | ||
| 035 | |a (NLM)38555449 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Tazhibi, Masih |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Focused ultrasound-mediated blood-brain barrier opening is safe and feasible with moderately hypofractionated radiotherapy for brainstem diffuse midline glioma |
| 264 | 1 | |c 2024 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 01.04.2024 | ||
| 500 | |a Date Revised 02.04.2024 | ||
| 500 | |a published: Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2024. The Author(s). | ||
| 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 | ||
| 520 | |a 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) | ||
| 520 | |a 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 | ||
| 520 | |a 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 Journal Article | |
| 650 | 4 | |a Blood–brain barrier opening | |
| 650 | 4 | |a Diffuse midline glioma | |
| 650 | 4 | |a Focused ultrasound | |
| 650 | 4 | |a Radiotherapy | |
| 700 | 1 | |a McQuillan, Nicholas |e verfasserin |4 aut | |
| 700 | 1 | |a Wei, Hong-Jian |e verfasserin |4 aut | |
| 700 | 1 | |a Gallitto, Matthew |e verfasserin |4 aut | |
| 700 | 1 | |a Bendau, Ethan |e verfasserin |4 aut | |
| 700 | 1 | |a Webster Carrion, Andrea |e verfasserin |4 aut | |
| 700 | 1 | |a Berg, Xander |e verfasserin |4 aut | |
| 700 | 1 | |a Kokossis, Danae |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Xu |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Zhiguo |e verfasserin |4 aut | |
| 700 | 1 | |a Jan, Chia-Ing |e verfasserin |4 aut | |
| 700 | 1 | |a Mintz, Akiva |e verfasserin |4 aut | |
| 700 | 1 | |a Gartrell, Robyn D |e verfasserin |4 aut | |
| 700 | 1 | |a Syed, Hasan R |e verfasserin |4 aut | |
| 700 | 1 | |a Fonseca, Adriana |e verfasserin |4 aut | |
| 700 | 1 | |a Pavisic, Jovana |e verfasserin |4 aut | |
| 700 | 1 | |a Szalontay, Luca |e verfasserin |4 aut | |
| 700 | 1 | |a Konofagou, Elisa E |e verfasserin |4 aut | |
| 700 | 1 | |a Zacharoulis, Stergios |e verfasserin |4 aut | |
| 700 | 1 | |a Wu, Cheng-Chia |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Journal of translational medicine |d 2003 |g 22(2024), 1 vom: 30. März, Seite 320 |w (DE-627)NLM142679194 |x 1479-5876 |7 nnns |
| 773 | 1 | 8 | |g volume:22 |g year:2024 |g number:1 |g day:30 |g month:03 |g pages:320 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1186/s12967-024-05096-9 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 22 |j 2024 |e 1 |b 30 |c 03 |h 320 | ||