Focused ultrasound mediated blood–brain barrier opening is safe and feasible in a murine pontine glioma model

Abstract Drug delivery in diffuse intrinsic pontine glioma is significantly limited by the blood-brain barrier (BBB). Focused ultrasound (FUS), when combined with the administration of microbubbles can effectively open the BBB permitting the entry of drugs across the cerebrovasculature into the brai...

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Autores principales:	Zachary K. Englander, Hong-Jian Wei, Antonios N. Pouliopoulos, Ethan Bendau, Pavan Upadhyayula, Chia-Ing Jan, Eleanora F. Spinazzi, Nina Yoh, Masih Tazhibi, Nicholas M. McQuillan, Tony J. C. Wang, Jeffrey N. Bruce, Peter Canoll, Neil A. Feldstein, Stergios Zacharoulis, Elisa E. Konofagou, Cheng-Chia Wu
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/e7a089d62acc48338378a525c21513c4
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spelling	oai:doaj.org-article:e7a089d62acc48338378a525c21513c42021-12-02T16:35:55ZFocused ultrasound mediated blood–brain barrier opening is safe and feasible in a murine pontine glioma model10.1038/s41598-021-85180-y2045-2322https://doaj.org/article/e7a089d62acc48338378a525c21513c42021-03-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-85180-yhttps://doaj.org/toc/2045-2322Abstract Drug delivery in diffuse intrinsic pontine glioma is significantly limited by the blood-brain barrier (BBB). Focused ultrasound (FUS), when combined with the administration of microbubbles can effectively open the BBB permitting the entry of drugs across the cerebrovasculature into the brainstem. Given that the utility of FUS in brainstem malignancies remains unknown, the purpose of our study was to determine the safety and feasibility of this technique in a murine pontine glioma model. A syngeneic orthotopic model was developed by stereotactic injection of PDGF-B+PTEN−/−p53−/− murine glioma cells into the pons of B6 mice. A single-element, spherical-segment 1.5 MHz ultrasound transducer driven by a function generator through a power amplifier was used with concurrent intravenous microbubble injection for tumor sonication. Mice were randomly assigned to control, FUS and double-FUS groups. Pulse and respiratory rates were continuously monitored during treatment. BBB opening was confirmed with gadolinium-enhanced MRI and Evans blue. Kondziela inverted screen testing and sequential weight lifting measured motor function before and after sonication. A subset of animals were treated with etoposide following ultrasound. Mice were either sacrificed for tissue analysis or serially monitored for survival with daily weights. FUS successfully caused BBB opening while preserving normal cardiorespiratory and motor function. Furthermore, the degree of intra-tumoral hemorrhage and inflammation on H&E in control and treated mice was similar. There was also no difference in weight loss and survival between the groups (p > 0.05). Lastly, FUS increased intra-tumoral etoposide concentration by more than fivefold. FUS is a safe and feasible technique for repeated BBB opening and etoposide delivery in a preclinical pontine glioma model.Zachary K. EnglanderHong-Jian WeiAntonios N. PouliopoulosEthan BendauPavan UpadhyayulaChia-Ing JanEleanora F. SpinazziNina YohMasih TazhibiNicholas M. McQuillanTony J. C. WangJeffrey N. BrucePeter CanollNeil A. FeldsteinStergios ZacharoulisElisa E. KonofagouCheng-Chia WuNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-10 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Zachary K. Englander Hong-Jian Wei Antonios N. Pouliopoulos Ethan Bendau Pavan Upadhyayula Chia-Ing Jan Eleanora F. Spinazzi Nina Yoh Masih Tazhibi Nicholas M. McQuillan Tony J. C. Wang Jeffrey N. Bruce Peter Canoll Neil A. Feldstein Stergios Zacharoulis Elisa E. Konofagou Cheng-Chia Wu Focused ultrasound mediated blood–brain barrier opening is safe and feasible in a murine pontine glioma model
description	Abstract Drug delivery in diffuse intrinsic pontine glioma is significantly limited by the blood-brain barrier (BBB). Focused ultrasound (FUS), when combined with the administration of microbubbles can effectively open the BBB permitting the entry of drugs across the cerebrovasculature into the brainstem. Given that the utility of FUS in brainstem malignancies remains unknown, the purpose of our study was to determine the safety and feasibility of this technique in a murine pontine glioma model. A syngeneic orthotopic model was developed by stereotactic injection of PDGF-B+PTEN−/−p53−/− murine glioma cells into the pons of B6 mice. A single-element, spherical-segment 1.5 MHz ultrasound transducer driven by a function generator through a power amplifier was used with concurrent intravenous microbubble injection for tumor sonication. Mice were randomly assigned to control, FUS and double-FUS groups. Pulse and respiratory rates were continuously monitored during treatment. BBB opening was confirmed with gadolinium-enhanced MRI and Evans blue. Kondziela inverted screen testing and sequential weight lifting measured motor function before and after sonication. A subset of animals were treated with etoposide following ultrasound. Mice were either sacrificed for tissue analysis or serially monitored for survival with daily weights. FUS successfully caused BBB opening while preserving normal cardiorespiratory and motor function. Furthermore, the degree of intra-tumoral hemorrhage and inflammation on H&E in control and treated mice was similar. There was also no difference in weight loss and survival between the groups (p > 0.05). Lastly, FUS increased intra-tumoral etoposide concentration by more than fivefold. FUS is a safe and feasible technique for repeated BBB opening and etoposide delivery in a preclinical pontine glioma model.
format	article
author	Zachary K. Englander Hong-Jian Wei Antonios N. Pouliopoulos Ethan Bendau Pavan Upadhyayula Chia-Ing Jan Eleanora F. Spinazzi Nina Yoh Masih Tazhibi Nicholas M. McQuillan Tony J. C. Wang Jeffrey N. Bruce Peter Canoll Neil A. Feldstein Stergios Zacharoulis Elisa E. Konofagou Cheng-Chia Wu
author_facet	Zachary K. Englander Hong-Jian Wei Antonios N. Pouliopoulos Ethan Bendau Pavan Upadhyayula Chia-Ing Jan Eleanora F. Spinazzi Nina Yoh Masih Tazhibi Nicholas M. McQuillan Tony J. C. Wang Jeffrey N. Bruce Peter Canoll Neil A. Feldstein Stergios Zacharoulis Elisa E. Konofagou Cheng-Chia Wu
author_sort	Zachary K. Englander
title	Focused ultrasound mediated blood–brain barrier opening is safe and feasible in a murine pontine glioma model
title_short	Focused ultrasound mediated blood–brain barrier opening is safe and feasible in a murine pontine glioma model
title_full	Focused ultrasound mediated blood–brain barrier opening is safe and feasible in a murine pontine glioma model
title_fullStr	Focused ultrasound mediated blood–brain barrier opening is safe and feasible in a murine pontine glioma model
title_full_unstemmed	Focused ultrasound mediated blood–brain barrier opening is safe and feasible in a murine pontine glioma model
title_sort	focused ultrasound mediated blood–brain barrier opening is safe and feasible in a murine pontine glioma model
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/e7a089d62acc48338378a525c21513c4
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Focused ultrasound mediated blood–brain barrier opening is safe and feasible in a murine pontine glioma model

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