Localized blood–brain barrier opening in infiltrating gliomas with MRI-guided acoustic emissions–controlled focused ultrasound
Menée sur quatre patients atteints d'un gliome infiltrant (âge moyen : 32,5 ans), cette étude évalue l'intérêt et la sécurité d'une approche thérapeutique, guidée par IRM, utilisant des ultrasons focalisés pour activer des microbulles intravasculaires et améliorer la perméabilité de la barrière hémato-encéphalique lors de traitements systémiques
The blood–brain barrier (BBB) is a critical obstacle to delivering most therapeutics into the brain. In this study, we report combined MRI, histological, and real-time acoustic emissions monitoring findings from a Phase 0 clinical trial examining microbubble-enhanced transcranial focused ultrasound for controlled BBB opening in patients with infiltrating gliomas. The data revealed the capability of this technology to provide safe, controlled, and tightly monitored BBB opening through the intact skull. Our findings demonstrate the capability of this technology to tune BBB opening in real-time, creating opportunities for improved treatment of brain tumors.Pharmacological treatment of gliomas and other brain-infiltrating tumors remains challenging due to limited delivery of most therapeutics across the blood–brain barrier (BBB). Transcranial MRI-guided focused ultrasound (FUS), an emerging technology for noninvasive brain treatments, enables transient opening of the BBB through acoustic activation of circulating microbubbles. Here, we evaluate the safety and utility of transcranial microbubble-enhanced FUS (MB-FUS) for spatially targeted BBB opening in patients with infiltrating gliomas. In this Phase 0 clinical trial (NCT03322813), we conducted comparative and quantitative analyses of FUS exposures (sonications) and their effects on gliomas using MRI, histopathology, microbubble acoustic emissions (harmonic dose [HD]), and fluorescence-guided surgery metrics. Contrast-enhanced MRI and histopathology indicated safe and reproducible BBB opening in all patients. These observations occurred using a power cycling closed feedback loop controller, with the power varying by nearly an order of magnitude on average. This range underscores the need for monitoring and titrating the exposure on a patient-by-patient basis. We found a positive correlation between microbubble acoustic emissions (HD) and MR-evident BBB opening (P = 0.07) and associated interstitial changes (P < 0.01), demonstrating the unique capability to titrate the MB-FUS effects in gliomas. Importantly, we identified a 2.2-fold increase of fluorescein accumulation in MB-FUS–treated compared to untreated nonenhancing tumor tissues (P < 0.01) while accounting for vascular density. Collectively, this study demonstrates the capabilities of MB-FUS for safe, localized, controlled BBB opening and highlights the potential of this technology to improve the surgical and pharmacologic treatment of brain tumors.All study data are included in the article and/or SI Appendix.