title: Enhanced brain distribution of carboplatin in a primate model after blood-brain barrier disruption using an implantable ultrasound device.
abstract: OBJECTIVE
  Glioblastoma is both the most common and aggressive primary brain tumor in adults. Carboplatin chemotherapy has shown only modest efficacy in progressive high-grade gliomas. The limited clinical efficacy of carboplatin may be due to its low concentration in tissue when the drug is delivered intravenously. The aim of this study was to assess whether the tissue concentration of intravenously administered carboplatin could be enhanced by ultrasound-induced blood-brain disruption in a primate model.
  
  
  METHODS
  Carboplatin was administered intravenously for 60 min to a single primate following blood-brain barrier opening induced by an implantable ultrasound device. Blood and brain samples were collected after animal killing, which occurred 60 min after the end of carboplatin administration. Platinum quantification in ultrafiltrate plasma and brain samples was performed using inductively coupled plasma mass spectrometry.
  
  
  RESULTS
  The brain concentration of platinum was highly enhanced (5.2×) in the 3.9 cm(3) region sonicated by the US beam, with a higher concentration in more vascularized anatomical structures. At 5 and 10 mm from the US beam axis, platinum concentrations were slightly enhanced (2.2× and 1.3× respectively).
  
  
  CONCLUSIONS
  This study demonstrates that BBB opening using an implantable ultrasound transducer enhances the brain distribution of carboplatin in a loco-regional manner. Such a treatment approach is of significant interest for the treatment of primary brain tumors and is under current evaluation in a phase 1 clinical trial (NCT02253212).
authors.affiliation: Pharmacology Department, Saint-Louis Hospital, AP-HP, 1 Avenue Claude Vellefaux, 75010, Paris, France. lauriane.goldwirt@aphp.fr.
authors.forename: Lauriane
authors.initials: L
authors.lastname: Goldwirt
authors.affiliation: CarThera Research Team, Brain and Spine Institute, Paris, France.
authors.forename: Michael
authors.initials: M
authors.lastname: Canney
authors.affiliation: CarThera Research Team, Brain and Spine Institute, Paris, France.|Neurosurgery Department, Pitie-Salpetriere Hospital, AP-HP, 75013, Paris, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Horodyckid
authors.affiliation: Toxicology Department, Lariboisiere Hospital, AP-HP, 75010, Paris, France.
authors.forename: Joel
authors.initials: J
authors.lastname: Poupon
authors.affiliation: Pharmacology Department, Saint-Louis Hospital, AP-HP, 1 Avenue Claude Vellefaux, 75010, Paris, France.|Faculté UFR de MÉDECINE Paris 7 Diderot, School of Medicine, Paris VII, Paris, France.
authors.forename: Samia
authors.initials: S
authors.lastname: Mourah
authors.affiliation: CarThera Research Team, Brain and Spine Institute, Paris, France.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Vignot
authors.affiliation: Inserm, U1032, LabTau, 69003, Lyon, France.
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Chapelon
authors.affiliation: CarThera Research Team, Brain and Spine Institute, Paris, France.|Neurosurgery Department, Pitie-Salpetriere Hospital, AP-HP, 75013, Paris, France.|School of Medicine, Paris VI Sorbonne University, Paris, France.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Carpentier
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001812:Blood-Brain Barrier / Q000378:metabolism*; D001921:Brain / Q000378:metabolism*; D016190:Carboplatin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D007262:Infusions, Intravenous; D013058:Mass Spectrometry / Q000379:methods; D048530:Papio anubis; D014018:Tissue Distribution; D014463:Ultrasonography / Q000379:methods*
chemical_list: D000970:Antineoplastic Agents; D016190:Carboplatin
keywords: Blood–brain barrier opening; Brain distribution; Carboplatin; Unfocused ultrasound