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|Title:||MRI ASSESSMENT OF KININ B1 RECEPTOR-MEDIATED BLOOD-BRAIN BARRIER DISRUPTION IN A F98 GLIOMA RAT MODEL|
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|Authors/Affiliations:||1 Jerome Cote*; 1 Martin Lepage; 1 Fernand Jr. Gobeil; 1 David Fortin; |
1 Université de Sherbrooke, QC, Canada
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|Content:||The blood-brain barrier (BBB) prevents the passage of drugs to the CNS through diffusion. Treatment of CNS neoplasia with chemotherapy is limited mostly because of delivery impediment related to this barrier and also by the natural or acquired resistance expressed by tumor cells. Multiple techniques have been studied to improve delivery across the BBB, e.g. mannitol intra-carotid infusion and focused-ultrasound. Recent evidence suggests that vascular B1 receptors (B1R) can regulate BBB permeability, including that of brain tumors. Dynamic magnetic resonance imaging (MRI) was used to monitor the selective increased of BBB induced by 3 different bradykinin agonists in F98 glioma-implanted Fischer rats: the natural B1 agonist (LDBK), a synthetic B1 receptor agonist (NG29), and a B2 synthetic agonist (R523).|
A total of 54 animals were used in this experiment. Glioma cells were implanted stereotactically in the region of the right caudate nucleus, and tumor development was allowed for 10 days. Experiments were conducted on anesthetized animals placed in a 7T animal RMN (Varian). A bolus of either Gd-DTPA (548 Da) or a larger Gd-based contrast agent (17 kDa) was injected i.v. (tail vein) with simultaneous monitoring of T1-weighted images for a period of 1h, in the purpose of determining the extent of the BBB permeabilization. Experiments were repeated 12h later, immediately following the BBB disruption procedure initiated by infusing in the right external carotid artery or in the left jugular vein one of the 3 agonists: LDBK (0.1 ml/min for 5 min), NG29 (2.5, 10 or 50 nmol/kg), or R523, (2.5, 10 or 50 nmol/kg). Anatomic MR images were analyzed for the presence or absence of contrast enhancement within and surrounding the tumor area, and were processed to yield quantitative contrast agent distribution volume (CADV). Since normal BBB prevents the passage of both contrast agents, the CADV reflects the volume where the BBB is leaky or has been permeabilized. Results were analyzed in terms of the enhancement differential between the first set of acquisition (contrast without agonist) vs the second set (contrast + agonist infusion) in each animal.
Our results suggest that intracarotid NG29 infusion modulates topographic uptake profiles of both contrast agents within rat glioma and brain tissue surrounding the tumor without affecting normal brain parenchyma from ipsi and contralateral hemispheres. Maximum CADV nearly doubled in the NG29-treated animals at the intermediate dose of 10 nmol/kg for both of the constrast agent. This latter effect was also observed with R523 but not with LDBK and was negated by co-infusion of excess B1R antagonist R892. Moreover, higher dose of B2 agonist R523 (50 nmol/kg) permeabilized the BBB non-selectively away from the tumor site, while all doses of B1 agonist remained selective for the tumor barrier and the brain around tumor area.
Our results support the use of synthetic B1R agonists as selective tumor BBB permeabilizers to improve delivery of chemotherapeutics in the CNS at the tumor and peritumoral area.
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