Induction of selective blood-tumor barrier permeability and macromolecular transport by a biostable kinin b1 receptor agonist in a glioma rat model

  • Treatment of malignant glioma with chemotherapy is limited mostly because of delivery impediment related to the blood-brain tumor barrier (BTB). B1 receptors (B1R), inducible prototypical G-protein coupled receptors (GPCR) can regulate permeability of vessels including possibly that of brain tumors. Here, we determine the extent of BTB permeability induced by the natural and synthetic peptide B1R agonists, LysdesArg9BK (LDBK) and SarLys[DPhe8]desArg9BK (NG29), in syngeneic F98 glioma-implanted Fischer rats. Ten days after tumor inoculation, we detected the presence of B1R on tumor cells and associated vasculature. NG29 infusion increased brain distribution volume and uptake profiles of paramagnetic probes (Magnevist and Gadomer) at tumoral sites (T1-weighted imaging). These effects were blocked by B1R antagonist and non-selective cyclooxygenase inhibitors, but not by B2R antagonist and non-selective nitric oxide synthase inhibitors. Consistent with MRI data, systemic co-administration of NG29 improved brain tumor delivery of Carboplatin chemotherapy (ICP-Mass spectrometry). We also detected elevated B1R expression in clinical samples of high-grade glioma. Our results documented a novel GPCR-signaling mechanism for promoting transient BTB disruption, involving activation of B1R and ensuing production of COX metabolites. They also underlined the potential value of synthetic biostable B1R agonists as selective BTB modulators for local delivery of different sized-therapeutics at (peri)tumoral sites.

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Metadaten
Author:Jérôme Côté, Veronica Bovenzi, Martin Savard, Céléna Dubuc, Audrey Fortier, Witold Neugebauer, Luc Tremblay, Werner Müller-EsterlORCiDGND, Ana-Maria Tsanaclis, Martin LepageORCiD, David Fortin, Fernand Gobeil
URN:urn:nbn:de:hebis:30:3-228201
DOI:https://doi.org/10.1371/journal.pone.0037485
ISSN:1932-6203
Pubmed Id:https://pubmed.ncbi.nlm.nih.gov/22629405
Parent Title (English):PLoS One
Publisher:PLoS
Place of publication:Lawrence, Kan.
Document Type:Article
Language:English
Date of Publication (online):2012/05/30
Date of first Publication:2012/05/21
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2012/05/30
Volume:7
Issue:(5): e37485
Page Number:17
HeBIS-PPN:302900411
Institutes:Medizin / Medizin
Dewey Decimal Classification:5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 570 Biowissenschaften; Biologie
6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Sammlung Biologie / Sondersammelgebiets-Volltexte
Licence (German):License LogoCreative Commons - Namensnennung 3.0