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Selective tumor blood-brain barrier opening with the kinin B2 receptor agonist [Phe(8)psi(CH(2)NH)Arg(9)]-BK in a F98 glioma rat model: an MRI study.

Cote J., Savard M., Bovenzi V., Dubuc C., Tremblay L., Tsanaclis A.M., Fortin D., Lepage M., Gobeil F. Jr.

Treatment of malignant glioma with chemotherapy is limited mostly because of delivery impediment related to the blood-brain barrier (BBB). One approach for transporting drugs across the BBB involves the activation of bradykinin-B2 receptors (BK-B2R). Our objective was to pharmacologically characterize the BBB permeability induced by the synthetic biostable BK-B2R analogue [Phe(8)psi(CH(2)NH)Arg(9)]-BK (R523) in F98 glioma-implanted Fischer rats. On day 10 post-inoculation, we detected the presence of B2R in the tumor cells and the peritumoral microvasculature (RT-PCR and immunohistochemistry). We assessed BBB permeability before and after the intracarotid (i.c.) infusion of R523 (0.1ml/min for 5min; 2.5, 10, and 50nmol/kg/min) using non-invasive dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) with the different sized-contrast agents Gd-DTPA (0.5kDa) and Gadomer (17kDa) (0.25mmol/kg via the caudal vein). T(1)-weighted images were analyzed for the presence or absence of contrast enhancement within and surrounding the tumor area and mathematically processed to yield a contrast agent distribution volume (CADV), which was used as an indicator of vascular permeability. Our results showed that the agonist R523 increased, in a dose-dependent manner, the CADV indexes of Gd-DTPA and Gadomer, with a maximum 2-fold increase in brain uptake of both CA. The increase in CADV induced by R523 (10nmol/kg/min) was prevented by the B2R antagonist HOE140 (20nmol/kg/min, i.c.) and the nitric oxide synthase inhibitor L-NA (5mg/kg, i.v.) but not by the B1R antagonist R892 (20nmol/kg/min, i.c.) or the cyclooxygenase inhibitor Meclofenamate (5mg/kg, i.v.). The BBB permeabilizing effect of R523 (10nmol/kg/min) lasted for <1h and was accompanied by a dose-related fall in arterial blood pressure. We concluded that R523 allows the extravasation of hydrophilic macromolecular agents (17kDa) into tumor tissues by inducing selective tumor BBB permeability via B2R- and NO-dependent mechanisms.

Neuropeptides 44:177-185(2010) [PubMed] [Europe PMC]

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