Focused ultrasound mediated blood\u2013brain barrier opening is safe and feasible in a murine pontine glioma model

Cheng-Chia Wu,Zachary K Englander,Neil A Feldstein,Pavan Upadhyayula,Tony J C Wang,Hong-Jian Wei,Nicholas M Mcquillan,Jeffrey N Bruce,Masih Tazhibi,Ethan Bendau,Nina Yoh,Antonios N Pouliopoulos,Elisa E Konofagou,Peter Canoll,Chia-Ing Jan,Eleanora F Spinazzi,Stergios Zacharoulis

doi:10.1038/s41598-021-85180-y

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.

Highlights

Drug delivery in diffuse intrinsic pontine glioma is significantly limited by the blood-brain barrier (BBB)
One of the major obstacles limiting the efficacy of systemic therapies in Diffuse intrinsic pontine glioma (DIPG) is the blood–brain barrier (BBB), which prohibits the delivery of most drugs to the central nervous system
SCDh was an order of magnitude higher than inertial cavitation doses (ICD) and two orders of magnitude higher than SCDu, verifying that stable microbubble activity drove the BBB opening process

Summary

Introduction

Drug delivery in diffuse intrinsic pontine glioma is significantly limited by the blood-brain barrier (BBB). Diffuse intrinsic pontine glioma (DIPG) is an aggressive pediatric brain tumor with a poor prognosis These devastating cancers are most commonly diagnosed in children around the ages of 6–7 years, and are responsible for the highest rate of brain tumor-related mortality in the pediatric p opulation[1,2]. One of the major obstacles limiting the efficacy of systemic therapies in DIPG is the blood–brain barrier (BBB), which prohibits the delivery of most drugs to the central nervous system To combat this problem, several treatment modalities have been developed to either penetrate or bypass the BBB, including convection-enhanced d elivery[6,7], high-dose c hemotherapy[8,9] and intraarterial injections[10]. No study has yet to show FUS-mediated BBB opening in a brainstem tumor

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