Overcoming the Blood–Brain Barrier with an Implantable Ultrasound Device

Abstract

Ultrasound-based blood-brain barrier disruption enhances drug delivery. To bypass the human skull, an implantable ultrasound emitter was developed, and proven safe and feasible in a first-in-human trial. Next development steps aim for larger field of disruption, quantification of drug levels, use of various drugs, and ultimately a pivotal trial demonstrating improved outcome.See related article by Idbaih et al., p. 3793 In this issue of Clinical Cancer Research, Idbaih and colleagues report on their phase I trial of opening the blood-brain barrier (BBB) with the use of an implantable ultrasound (1). Infiltrative gliomas and glioblastoma in particular, remain an incurable disease. As numerous novel therapeutic approaches have failed in controlled clinical trials, temozolomide remains the first-line drug in the treatment of these tumors, which is in part explained by its good penetration across the BBB. Indeed, the BBB is a major impediment to drug therapy of brain tumors, and thus, the technology evaluated on this trial overcomes such limitation.Pulsed ultrasound, when used in combination with intravenous injection of microbubbles, transiently disrupts the BBB. This technology has been around for some time, and shown to enhance delivery of antitumoral agents to the brain in a multitude of preclinical models. However, translation of this approach into patients requires the ultrasonic waves to either penetrate or bypass the relatively thick human skull. Our French colleagues take it to a new level by implanting the ultrasound emitter into a window on the patients' skull, thus overcoming the intrinsic resistance of the skull when using conventional external systems. This system has allowed easy and repeat opening of the BBB. The ultrasound emitter activates microbubbles that are simultaneously administered intravenously. By this means, the BBB is mechanically disrupted, and diffusion of larger and polar molecules into the brain becomes feasible. The BBB opening is reversible and lasts for several hours after the sonication.Here, Idbaih and colleagues have successfully treated 19 patients with BBB disruption using the implantable ultrasound emitter, and concomitant administration of the cytotoxic chemotherapy agent carboplatin (1, 2). They visualize the opening of the BBB as temporary extravasation of gadolinium on MRI performed immediately after each sonication. They report "successful" BBB opening in 52 of 65 sonication sessions. Overall, treatment-

Ultrasound-mediated Delivery of Paclitaxel for Glioma: A Comparative Study of Distribution, Toxicity, and Efficacy of Albumin-bound Versus Cremophor Formulations

“…On the other hand, the most recent iteration of the implantable US device developed by Carthera, Sonocloud-9, features nine US transducer heads that are designed to sonicate the tumor and surrounding infiltrative region. [40] As US-mediated BBB disruption for drug delivery moves from pre-clinical to clinical studies, the ability to quantify the concentration of the therapeutic agent delivered into the brain parenchyma via US-mediated BBB opening may be of importance. [40] Currently, BBB disruption by US is validated by the use of Evan's Blue injection in animal models or by MRI gadolinium contrast-enhancement in patients.…”

“…[40] As US-mediated BBB disruption for drug delivery moves from pre-clinical to clinical studies, the ability to quantify the concentration of the therapeutic agent delivered into the brain parenchyma via US-mediated BBB opening may be of importance. [40] Currently, BBB disruption by US is validated by the use of Evan's Blue injection in animal models or by MRI gadolinium contrast-enhancement in patients. [19,41] One drawback to MRI visualization of BBB opening is this method does not allow for real-time tissue sampling of regions of US BBB disruption.…”

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“…For instance, ongoing trials are evaluating doxorubicin for glioblastomas using MRI-guided laser therapy to open the blood-brain barrier and enhance the penetration of this drug to the human brain in children and adults ( NCT02372409 and NCT01851733 clinicaltrials.gov ). On the other hand, ultrasound- based opening of the blood-brain barrier is an emerging technology to enhance drug delivery to the brain for glioblastomas ( 47 , 48 , 49 ). This approach is now being tested on several clinical trials ( 49 , 50 , 53 , 51 , 52 ) and has been shown to be feasible and effective for doxorubicin delivery in several pre-clinical models of gliomas and in some early phase clinical trials ( 50 – 53 ).…”

Focused Ultrasound Combined with Microbubbles in Central Nervous System Applications

“…However, a major inconvenience is that the implantation of the transducer disc needs to be determined based on the predicted disease progression. A new version of the system involves implanting nine emitters while creating multiple bur holes so that a wider area can be covered to vary or widen the BBBO region for better disease control [ 97 ].…”