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

• Published in: Neuropeptides (Edinburgh) Vol. 44; no. 2; pp. 177 - 185
• Main Authors: Cote, Jerome, Savard, Martin, Bovenzi, Veronica, Dubuc, Celena, Tremblay, Luc, Tsanaclis, Ana Maria, tin, David, Lepage, Martin, Gobeil, Fernand
• Format: Journal Article
• Language: English
• Published: 01-04-2010
• ISSN: 0143-4179
• DOI: 10.1016/j.npep.2009.12.009

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 super(8)[psi](CH sub(2)NH)Arg super(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 (0.1 ml/min for 5 min; 2.5, 10, and 50 nmol/kg/min) using non-invasive dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) with the different sized-contrast agents Gd-DTPA (0.5 kDa) and Gadomer (17 kDa) (0.25 mmol/kg via the caudal vein). T sub(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 (10 nmol/kg/min) was prevented by the B2R antagonist HOE140 (20 nmol/kg/min, i.c.) and the nitric oxide synthase inhibitor L-NA (5 mg/kg, i.v.) but not by the B1R antagonist R892 (20 nmol/kg/min, i.c.) or the cyclooxygenase inhibitor Meclofenamate (5 mg/kg, i.v.). The BBB permeabilizing effect of R523 (10 nmol/kg/min) lasted for <1 h and was accompanied by a dose-related fall in arterial blood pressure. We concluded that R523 allows the extravasation of hydrophilic macromolecular agents ([less-than-or-equals, slant]17 kDa) into tumor tissues by inducing selective tumor BBB permeability via B2R- and NO-dependent mechanisms.