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

• Published in: Scientific reports Vol. 11; no. 1; p. 6521
• Main Authors: Englander, Zachary K., Wei, Hong-Jian, Pouliopoulos, Antonios N., Bendau, Ethan, Upadhyayula, Pavan, Jan, Chia-Ing, Spinazzi, Eleanora F., Yoh, Nina, Tazhibi, Masih, McQuillan, Nicholas M., Wang, Tony J. C., Bruce, Jeffrey N., Canoll, Peter, Feldstein, Neil A., Zacharoulis, Stergios, Konofagou, Elisa E., Wu, Cheng-Chia
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 22-03-2021; Nature Publishing Group; Nature Portfolio
• Subjects: 631/67/1922; 631/67/2332; Animals; Biological Transport - drug effects; Blood-brain barrier; Blood-Brain Barrier - drug effects; Brain cancer; Brain stem; Brain Stem - diagnostic imaging; Brain Stem - drug effects; Brain Stem Neoplasms - diagnostic imaging; Brain Stem Neoplasms - drug therapy; Brain Stem Neoplasms - genetics; Brain Stem Neoplasms - pathology; Disease Models, Animal; Drug delivery; Drug Delivery Systems; Etoposide; Etoposide - pharmacology; Evans Blue - pharmacology; Gadolinium; Gadolinium - pharmacology; Glioma; Glioma - diagnostic imaging; Glioma - drug therapy; Glioma - genetics; Glioma - pathology; Glioma cells; Hemorrhage; Humanities and Social Sciences; Humans; Inflammation; Injection; Intravenous administration; Magnetic Resonance Imaging; Mice; multidisciplinary; p53 Protein; Platelet-derived growth factor; Pons; Pons - diagnostic imaging; Pons - drug effects; Proto-Oncogene Proteins c-sis - genetics; Proto-Oncogene Proteins c-sis - pharmacology; PTEN Phosphohydrolase - genetics; PTEN Phosphohydrolase - pharmacology; PTEN protein; Science; Science (multidisciplinary); Sonication; Tissue analysis; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - pharmacology; Ultrasonic imaging; Ultrasonography; Ultrasound
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-021-85180-y

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.