Targeting diffuse midline gliomas: The promise of focused ultrasound-mediated blood-brain barrier opening.

Authors: Martinez PJ, Green AL, Borden MA

Diffuse midline gliomas (DMGs), including diffuse intrinsic pontine glioma, have among the highest mortality rates of all childhood cancers, despite recent advancements in cancer therapeutics. This is partly because, unlike some CNS tumors, the blood-brain barrier (BBB) of DMG tumor vessels remains intact. The BBB prevents the permeation of many molecular therapies into the brain parenchyma, where the cancer cells reside. Focused ultrasound (FUS) with microbubbles has recently emerged as an innovative and exciting technology that non-invasively permeabilizes the BBB in a small focal region with millimeter precision. In this review, current treatment methods and biological barriers to treating DMGs are discussed. State-of-the-art FUS-mediated BBB opening is then examined, with a focus on the effects of various ultrasound parameters and the treatment of DMGs.

Introduction

Purpose drug delivery with BBB opening

Outcomes and Safety

Summary of Outcomes This review summarizes the use of focused ultrasound with microbubbles to temporarily open the blood-brain barrier for drug delivery in diffuse midline gliomas (including DIPG). Preclinical studies have successfully delivered doxorubicin, etoposide, panobinostat, and other agents to the brainstem in mouse models, with up to 8-fold increased drug accumulation and some survival benefit. Key FUS parameters include frequency 1.5-1.78 MHz, PNP 0.25-0.75 MPa, PRF 0.5-10 Hz, PL 0.67-120 ms, sonication duration 18-180 s. Microbubbles used include Definity, SonoVue, and custom DSPC-PEG formulations. Clinical trials with ExAblate and NaviFUS are ongoing. The review also discusses BBB physiology, treatment barriers, and MB+FUS technology optimization.

Brain Region

Targeted brain region(s) Not specified

Ultrasound Parameters

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