title: Ultrasound-induced opening of the blood-brain barrier to enhance temozolomide and irinotecan delivery: an experimental study in rabbits.
abstract: OBJECT The blood-brain barrier (BBB) limits the intracerebral penetration of drugs and brain tumor treatment efficacy. The effect of ultrasound-induced BBB opening on the intracerebral concentration of temozolomide (TMZ) and irinotecan (CPT-11) was assessed. METHODS This study was performed using 34 healthy New Zealand rabbits. Half had unilateral BBB opening, and half served as controls. Sonications were performed by pulsing a 1.05-MHz planar ultrasound transducer with a duty cycle of 2.5% and an in situ acoustic pressure level of 0.6 MPa after injection of a microbubble ultrasound contrast agent. Drugs were injected either 5 minutes before (ChemoPreUS) or 15 minutes after (ChemoPostUS) the ultrasound sonication. The plasma and intracerebral concentrations of both drugs were quantified using ultra-performance liquid chromatography. RESULTS The mean intracerebral tissue-to-plasma drug concentration ratio in the control hemispheres was 34% for TMZ and 2% for CPT-11. After BBB opening, these values increased by up to 21% for TMZ and up to 178% for CPT-11. Intracerebral concentrations of drugs were enhanced in regions where the BBB was opened compared with the contralateral hemisphere (p < 0.01 and p < 0.0001 for CPT-11, p = 0.02 and p = 0.03 for TMZ, in ChemoPreUS and ChemoPostUS, respectively) and compared with the control group (p < 0.001 and p < 0.0001 for CPT-11, p < 0.01 and p = 0.02 for TMZ, in ChemoPreUS and ChemoPostUS, respectively). The intracerebral distribution of drugs was heterogeneous, depending on the distance from the ultrasound source. CONCLUSIONS Ultrasound-induced opening of the BBB significantly enhances the intracerebral concentration of both TMZ and CPT-11 in rabbits.
authors.affiliation: CarThera Research Team, Brain and Spine Institute, Paris;|Department of Neurosurgery, Assistance Publique-Hopitaux de Paris, Necker Enfants Malades Hospital, Paris;
authors.forename: Kevin
authors.initials: K
authors.lastname: Beccaria
authors.affiliation: CarThera Research Team, Brain and Spine Institute, Paris;
authors.forename: Michael
authors.initials: M
authors.lastname: Canney
authors.affiliation: Clinical Pharmacy Department, College of Pharmacy, Paris Sud University, Chatenay Malabry;
authors.forename: Lauriane
authors.initials: L
authors.lastname: Goldwirt
authors.affiliation: Clinical Pharmacy Department, College of Pharmacy, Paris Sud University, Chatenay Malabry;
authors.forename: Christine
authors.initials: C
authors.lastname: Fernandez
authors.affiliation: Laboratory of Biosurgical Research, University of Paris Descartes, Sorbonne Paris Cite, Paris;
authors.forename: Julie
authors.initials: J
authors.lastname: Piquet
authors.affiliation: INSERM U970, Centre de recherche cardiovasculaire de Paris-Epidémiologie cardiovasculaire, Paris;
authors.forename: Marie-Cécile
authors.initials: MC
authors.lastname: Perier
authors.affiliation: INSERM U1032, LabTau, University of Lyon;
authors.forename: Cyril
authors.initials: C
authors.lastname: Lafon
authors.affiliation: INSERM U1032, LabTau, University of Lyon;
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Chapelon
authors.affiliation: Assistance Publique-Hopitaux de Paris, Pitie Salpetriere Hospital, Department of Neurosurgery, Paris; and.|Paris 6 Sorbonne University, School of Medicine, Paris, France.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Carpentier
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D001774:Blood Chemical Analysis; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000378:metabolism*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D002851:Chromatography, High Pressure Liquid; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D000077146:Irinotecan; D008297:Male; D045423:Microbubbles; D011817:Rabbits; D015203:Reproducibility of Results; D000077204:Temozolomide; D014463:Ultrasonography / Q000379:methods*
chemical_list: D000970:Antineoplastic Agents; D000077146:Irinotecan; D003606:Dacarbazine; D002166:Camptothecin; D000077204:Temozolomide
keywords: BBB = blood-brain barrier; BCNU = 1,3-bis(2-chloroethyl)-1-nitrosourea; CPT-11 = irinotecan; IV = intravenous; MGMT = O-6-methylguanine-DNA methyltransferase; TMZ = temozolomide; UCA = ultrasound contrast agent; blood-brain barrier; brain tumors; drug delivery; irinotecan; oncology; temozolomide; ultrasound