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Cancer Chemother Pharmacol. 2016 Jan;77(1):211-6. doi: 10.1007/s00280-015-2930-5. Epub 2015 Dec 8.

Enhanced brain distribution of carboplatin in a primate model after blood-brain barrier disruption using an implantable ultrasound device.

Author information

1
Pharmacology Department, Saint-Louis Hospital, AP-HP, 1 Avenue Claude Vellefaux, 75010, Paris, France. lauriane.goldwirt@aphp.fr.
2
CarThera Research Team, Brain and Spine Institute, Paris, France.
3
Neurosurgery Department, Pitie-Salpetriere Hospital, AP-HP, 75013, Paris, France.
4
Toxicology Department, Lariboisiere Hospital, AP-HP, 75010, Paris, France.
5
Pharmacology Department, Saint-Louis Hospital, AP-HP, 1 Avenue Claude Vellefaux, 75010, Paris, France.
6
Faculté UFR de MÉDECINE Paris 7 Diderot, School of Medicine, Paris VII, Paris, France.
7
Inserm, U1032, LabTau, 69003, Lyon, France.
8
School of Medicine, Paris VI Sorbonne University, Paris, France.

Abstract

PURPOSE:

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).

KEYWORDS:

Blood–brain barrier opening; Brain distribution; Carboplatin; Unfocused ultrasound

PMID:
26645405
DOI:
10.1007/s00280-015-2930-5
[Indexed for MEDLINE]

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