Blood-Brain Barrier Opening in Primary Brain Tumors with Non-invasive MR-Guided Focused Ultrasound: A Clinical Safety and Feasibility Study

Abstract

The blood-brain barrier (BBB) has long limited therapeutic access to brain tumor and peritumoral tissue. In animals, MR-guided focused ultrasound (MRgFUS) with intravenously injected microbubbles can temporarily and repeatedly disrupt the BBB in a targeted fashion, without open surgery. Our objective is to demonstrate safety and feasibility of MRgFUS BBB opening with systemically administered chemotherapy in patients with glioma in a phase I, single-arm, open-label study. Five patients with previously confirmed or suspected high-grade glioma based on imaging underwent the MRgFUS in conjunction with administration of chemotherapy (n = 1 liposomal doxorubicin, n = 4 temozolomide) one day prior to their scheduled surgical resection. Samples of “sonicated” and “unsonicated” tissue were measured for the chemotherapy by liquid-chromatography-mass spectrometry. Complete follow-up was three months. The procedure was well-tolerated, with no adverse clinical or radiologic events related to the procedure. The BBB within the target volume showed radiographic evidence of opening with an immediate 15–50% increased contrast enhancement on T1-weighted MRI, and resolution approximately 20 hours after. Biochemical analysis of sonicated versus unsonicated tissue suggest chemotherapy delivery is feasible. In this study, we demonstrated transient BBB opening in tumor and peritumor tissue using non-invasive low-intensity MRgFUS with systemically administered chemotherapy was safe and feasible. The characterization of therapeutic delivery and clinical response to this treatment paradigm requires further investigation.

Glymphatics Visualization after Focused Ultrasound‐Induced Blood–Brain Barrier Opening in Humans

“…Secondary biologic effects have also been associated with FUS, such as increased neurogenesis and transient microglial activation . Combined with real‐time neuroimaging, magnetic resonance–guided FUS (MRgFUS) allows targeted BBB opening with stereotactic precision, with pilot studies recently published in AD and glioblastoma patients . MRgFUS creates an opportunity to study the glymphatic efflux system in vivo noninvasively.…”

Focused ultrasound opening of the blood–brain barrier for treatment of Parkinson's disease

“…7 In its human applications so far (and carried out with coadministration of a microbubble contrast agent 8 ), FUS has been efficacious at facilitating oncological chemotherapy in the human brain. 9 This clinical experience is likely to guide the way forward for clinical applications of treatments for PD. A workshop organized by the Focused Ultrasound Foundation was held in November 2018 for a state-ofthe-art discussion about trans-BBB therapeutics for PD using FUS technology.…”

“…FUS has the unique benefit of offering precisely controlled localization of drug delivery in an awake patient . In its human applications so far (and carried out with coadministration of a microbubble contrast agent), FUS has been efficacious at facilitating oncological chemotherapy in the human brain . This clinical experience is likely to guide the way forward for clinical applications of treatments for PD.…”

Parkinson's disease gene therapy: Will focused ultrasound and nanovectors be the next frontier?

“…18 Such approaches have also been used to successfully deliver neurotrophic factors and genes to the brains of rodents. [19][20][21] Importantly, the BBB opening with MBs and ultrasound has entered clinical trials for patients with Alzheimer's disease and primary brain tumors [22][23][24] and shows an excellent safety profile thus far.…”