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 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.

Focused ultrasound for the treatment of glioblastoma

“…Although there are some portions of gliomas that display magnetic resonance imaging (MRI) contrast enhancement suggesting "leaky" vessels that allow extravasation of large molecules, it is known that tumor cells extend far beyond the borders Adjuvant TMZ of these enhancing areas; therefore, the intact BBB remains an obstacle in the effective delivery of anti-cancer therapies [2]. When combined with microbubble administration, lowintensity focused ultrasound is a promising technique for BBB opening (BBBO) that has been widely studied across preclinical models with encouraging results [3][4][5] (Fig. 2B).…”

New Developments in the Pathogenesis, Therapeutic Targeting, and Treatment of H3K27M-Mutant Diffuse Midline Glioma

“…FUS increased intratumoral drug concentration up to fivefold in murine models with minimal toxicity. In orthotopic murine models of DMG, MRgFUS improved drug delivery to the tumor and decreased tumor growth [ 84 , 85 , 86 , 87 ]. Overall, these trials suggest that tumor-localized treatment may be an attractive option for H3K27M DMG and synergize with conventional chemotherapy and radiation regimens.…”

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“…Due to the absence of a similar device in the authors' setting, an inverted screen grip strength test was used [24]. This test has been adopted by multiples studies as a functional assessment of rodents in various disease models [37,38]. Upon osteoarthritis induction, a significant decrease in grip strength was noted for all rats, except the T + G group.…”