Safety and Feasibility of Repeated and Transient Blood–Brain Barrier Disruption by Pulsed Ultrasound in Patients with Recurrent Glioblastoma

Abstract

Purpose: The blood-brain barrier (BBB) limits the efficacy of drug therapies for glioblastoma (GBM). Preclinical data indicate that low-intensity pulsed ultrasound (LIPU) can transiently disrupt the BBB and increase intracerebral drug concentrations.Patients and Methods: A first-in-man, single-arm, singlecenter trial (NCT02253212) was initiated to investigate the transient disruption of the BBB in patients with recurrent GBM. Patients were implanted with a 1-MHz, 11.5-mm diameter cranial ultrasound device (SonoCloud-1, CarThera). The device was activated monthly to transiently disrupt the BBB before intravenous carboplatin chemotherapy.Results: Between 2014 and 2016, 21 patients were registered for the study and implanted with the SonoCloud-1; 19 patients received at least one sonication. In 65 ultrasound sessions, BBB disruption was visible on T1w MRI for 52 sonications. Treatment-related adverse events observed were transient and manageable: a transient edema at H1 and at D15. No carboplatin-related neurotoxicity was observed. Patients with no or poor BBB disruption (n ¼ 8) visible on MRI had a median progression-free survival (PFS) of 2.73 months, and a median overall survival (OS) of 8.64 months. Patients with clear BBB disruption (n ¼ 11) had a median PFS of 4.11 months, and a median OS of 12.94 months.Conclusions: SonoCloud-1 treatments were well tolerated and may increase the effectiveness of systemic drug therapies, such as carboplatin, in the brain without inducing neurotoxicity. NOTE: Data are median (range). Idbaih et al. NOTE: The occurrence of each AE is listed as well as the total number of patients affected, as some patients might have experienced the same AE multiple times over the course of therapy.Blood-Brain Barrier Disruption by Ultrasound in GBM www.aacrjournals.org

Focused Ultrasound Preconditioning for Augmented Nanoparticle Penetration and Efficacy in the Central Nervous System

“…Activating circulating microbubbles (MBs) with MR image‐guided focused ultrasound (FUS) transiently opens the BBB in a spatially‐targeted manner, with BBB integrity restored within 4–6 h after treatment . This strategy has been shown to be safe, and multiple clinical trials utilizing FUS and MBs for BBB opening in patients have either been completed or are underway . Our group has demonstrated that this approach facilitates the delivery of BPN, with diameters ranging from 40 to 65 nm, into the CNS .…”

Recurrent or Refractory High-Grade Gliomas Treated by Convection-Enhanced Delivery of a TGFβ2-Targeting RNA Therapeutic: A Post-Hoc Analysis with Long-Term Follow-Up

“…While a CED system has been used to deliver OT101 in clinical trials to date, it may also be possible in the future to administer OT101 without a neurosurgical intervention as a payload in a nanoformulation that can cross the blood-brain-barrier (BBB) via active transport mechanisms employing receptor-mediated or adsorption-mediated endocytosis, including but not limited to poly(lactic-co-glycolic acid) (PLGA)-based polymeric nanoparticles and targeted nanoliposomes [39,40]. It may also be possible to achieve therapeutic CNS delivery of OT101 by using clinically available methods of transient and repeated BBB disruption, such as the MRI-guided focused ultrasound-mediated drug delivery platform [41] or low intensity pulsed ultrasound (LIPU) using a cranial ultrasound device that can be activated prior to drug administration at [42,43].…”

This was the year that was: brain barriers and brain fluid research in 2019

“…Focused ultrasound has been used to transiently open the BBB to enhance drug delivery in vivo in animal models [167,168] and, as discussed below, in the clinic [169,170]. An interesting further use of ultrasoundinduced barrier disruption has been to allow entry of a contrast agent into the brain of patients which can then be tracked non-invasively by MRI to examine clearance routes (e.g.…”