title: 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.
abstract: 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.
authors.affiliation: Department of Nuclear Medicine and Radiobiology, Université de Sherbrooke, Sherbrooke, QC, Canada J1H 5N4.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Côté
authors.forename: Martin
authors.initials: M
authors.lastname: Savard
authors.forename: Veronica
authors.initials: V
authors.lastname: Bovenzi
authors.forename: Céléna
authors.initials: C
authors.lastname: Dubuc
authors.forename: Luc
authors.initials: L
authors.lastname: Tremblay
authors.forename: Ana Maria
authors.initials: AM
authors.lastname: Tsanaclis
authors.forename: David
authors.initials: D
authors.lastname: Fortin
authors.forename: Martin
authors.initials: M
authors.lastname: Lepage
authors.forename: Fernand
authors.initials: F
authors.lastname: Gobeil
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000378:metabolism; D001920:Bradykinin / Q000031:analogs & derivatives* / Q000494:pharmacology; D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D002199:Capillary Permeability / Q000502:physiology*; D005910:Glioma / Q000188:drug therapy / Q000378:metabolism*; D007150:Immunohistochemistry; D008279:Magnetic Resonance Imaging; D008297:Male; D009368:Neoplasm Transplantation; D009569:Nitric Oxide / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D043782:Receptor, Bradykinin B2 / Q000819:agonists / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D043782:Receptor, Bradykinin B2; C059243:bradykinin, Phe(8)-psi-CH2NH-Arg(9)-; D009569:Nitric Oxide; D001920:Bradykinin