Clinical trial of blood-brain barrier disruption by pulsed ultrasound.
The blood-brain barrier (BBB) limits the delivery of systemically administered drugs to the brain. Methods to circumvent the BBB have been developed, but none are used in standard clinical practice. The lack of adoption of existing methods is due to procedural invasiveness, serious adverse effects, and the complications associated with performing such techniques coincident with repeated drug administration, which is customary in chemotherapeutic protocols. Pulsed ultrasound, a method for disrupting the BBB, was shown to effectively increase drug concentrations and to slow tumor growth in preclinical studies. We now report the interim results of an ultrasound dose-escalating phase 1/2a clinical trial using an implantable ultrasound device system, SonoCloud, before treatment with carboplatin in patients with recurrent glioblastoma (GBM). The BBB of each patient was disrupted monthly using pulsed ultrasound in combination with systemically injected microbubbles. Contrast-enhanced magnetic resonance imaging (MRI) indicated that the BBB was disrupted at acoustic pressure levels up to 1.1 megapascals without detectable adverse effects on radiologic (MRI) or clinical examination. Our preliminary findings indicate that repeated opening of the BBB using our pulsed ultrasound system, in combination with systemic microbubble injection, is safe and well tolerated in patients with recurrent GBM and has the potential to optimize chemotherapy delivery in the brain.
Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpitaux Universitaires La Pitié-Salpêtrière, Service de Neurochirurgie, F-75013 Paris, France. Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, F-75013 Paris, France. alexandre.carpentier@aphp.fr.
Alexandre
A
Carpentier
CarThera, Institut du Cerveau et de la Moelle épinière (ICM), Paris F-75013, France.
Michael
M
Canney
CarThera, Institut du Cerveau et de la Moelle épinière (ICM), Paris F-75013, France.
Alexandre
A
Vignot
Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpitaux Universitaires La Pitié-Salpêtrière, Service de Neurochirurgie, F-75013 Paris, France. Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, F-75013 Paris, France.
Vincent
V
Reina
Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpitaux Universitaires La Pitié-Salpêtrière, Service de Neurochirurgie, F-75013 Paris, France.
Kevin
K
Beccaria
Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpitaux Universitaires La Pitié-Salpêtrière, Service de Neurochirurgie, F-75013 Paris, France.
Catherine
C
Horodyckid
Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpitaux Universitaires La Pitié-Salpêtrière, Service de Neurochirurgie, F-75013 Paris, France. Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, F-75013 Paris, France.
Carine
C
Karachi
AP-HP, Hôpitaux Universitaires La Pitié-Salpêtrière-Charles Foix, Service de Neuroradiologie, F-75013 Paris, France.
Delphine
D
Leclercq
INSERM, U1032, LabTau, Lyon F-69003, France.
Cyril
C
Lafon
INSERM, U1032, LabTau, Lyon F-69003, France.
Jean-Yves
JY
Chapelon
Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpitaux Universitaires La Pitié-Salpêtrière, Service de Neurochirurgie, F-75013 Paris, France.
Laurent
L
Capelle
Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpitaux Universitaires La Pitié-Salpêtrière, Service de Neurochirurgie, F-75013 Paris, France. Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, F-75013 Paris, France.
Philippe
P
Cornu
Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, F-75013 Paris, France. INSERM, U 1127, F-75013 Paris, France. CNRS, UMR 7225, F-75013, Paris, France. ICM, F-75013 Paris, France. AP-HP, Hôpitaux Universitaires La Pitié-Salpêtrière-Charles Foix, Service de Neurologie 2-Mazarin, F-75013 Paris, France.
Marc
M
Sanson
Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, F-75013 Paris, France. INSERM, U 1127, F-75013 Paris, France. CNRS, UMR 7225, F-75013, Paris, France. ICM, F-75013 Paris, France. AP-HP, Hôpitaux Universitaires La Pitié-Salpêtrière-Charles Foix, Service de Neurologie 2-Mazarin, F-75013 Paris, France.
Khê
K
Hoang-Xuan
Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, F-75013 Paris, France. INSERM, U 1127, F-75013 Paris, France. CNRS, UMR 7225, F-75013, Paris, France. ICM, F-75013 Paris, France. AP-HP, Hôpitaux Universitaires La Pitié-Salpêtrière-Charles Foix, Service de Neurologie 2-Mazarin, F-75013 Paris, France.
Jean-Yves
JY
Delattre
Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, F-75013 Paris, France. INSERM, U 1127, F-75013 Paris, France. CNRS, UMR 7225, F-75013, Paris, France. ICM, F-75013 Paris, France. AP-HP, Hôpitaux Universitaires La Pitié-Salpêtrière-Charles Foix, Service de Neurologie 2-Mazarin, F-75013 Paris, France.
Ahmed
A
Idbaih
D001812:Blood-Brain Barrier / Q000187:drug effects / Q000528:radiation effects* / Q000601:surgery; D001921:Brain / Q000187:drug effects / Q000528:radiation effects / Q000601:surgery; D016190:Carboplatin / Q000627:therapeutic use; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy / Q000601:surgery; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D045423:Microbubbles; D000069453:Ultrasonic Waves
D016190:Carboplatin