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Neurosurg Focus. 2020 Jan 1;48(1):E10. doi: 10.3171/2019.10.FOCUS19726.

Blood-brain barrier disruption with low-intensity pulsed ultrasound for the treatment of pediatric brain tumors: a review and perspectives.

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1Department of Pediatric Neurosurgery, Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris 5 University, Paris.
2CarThera, Institut du Cerveau et de la Moelle épinière (ICM), Paris.
3Department of Pediatric Oncology, Gustave-Roussy, Université Paris-Sud, Université Paris-Saclay, Villejuif.
4UMR8203 "Vectorologie et Thérapeutiques Anticancéreuses," CNRS, Gustave-Roussy, Université Paris-Sud, Université Paris-Saclay, Villejuif; and.
5Department of Neurosurgery, Sorbonne Université, UPMC Paris 6, AP-HP, Hôpitaux Universitaires La Pitié-Salpêtrière, Paris, France.


Pediatric brain tumors are the most common solid tumor and the first cause of cancer death in childhood, adolescence, and young adulthood. Current treatments are far from optimal in most of these tumors and the prognosis remains dismal for many of them. One of the main causes of the failure of current medical treatments is in part due to the existence of the blood-brain barrier (BBB), which limits drug delivery to tumors. Opening of the BBB with low-intensity pulsed ultrasound (LIPU) has emerged during the last 2 decades as a promising technique for enhancing drug delivery to the brain. In preclinical models, enhanced delivery of a wide range of therapeutic agents, from low-molecular-weight drugs, to antibodies and immune cells, has been observed as well as tumor control and increased survival. This technique has recently entered clinical trials with extracranial and intracranial devices. The safety and feasibility of this technique has furthermore been shown in patients treated monthly for recurrent glioblastoma receiving carboplatin chemotherapy. In this review, the characteristics of the BBB in the most common pediatric brain tumors are reviewed. Then, principles and mechanisms of BBB disruption with ultrasound (US) are summarized and described at the histological and biological levels. Lastly, preclinical studies that have used US-induced BBB opening in tumor models, recent clinical trials, and the potential use of this technology in pediatrics are provided.


ABC = ATP-binding cassette; BBB = blood-brain barrier; BBBD = BBB disruption; BCRP = breast cancer resistance protein; DIPG = diffuse intrinsic pontine glioma; GBM = glioblastoma; LIPU = low-intensity pulsed US; NHP = nonhuman primate; NK = natural killer; OS = overall survival; PFS = progression-free survival; US = ultrasound; blood-brain barrier; brain tumor; drug delivery; low-intensity pulsed ultrasound; pHGG = pediatric high-grade glioma; pediatric


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