Abstract
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 (T 1-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.
Highlights
Major advances in medical and surgical treatments in the last few decades have increased the overall survival of patients with many types of cancers with the exception of those in the central nervous system (CNS) [1,2]
We explored whether a B1 receptors (B1R) agonist can enhance bioavailability of the chemotherapeutic agent Carboplatin in brain tumor tissues using inductively coupled plasma-mass spectroscopy (ICP-MS)
Similar transmission electron microscopy (TEM) results were obtained with the anti-B1R antibody RC72
Summary
Major advances in medical and surgical treatments in the last few decades have increased the overall survival of patients with many types of cancers with the exception of those in the central nervous system (CNS) [1,2]. High grade malignant gliomas (WHO grades III and IV) are characterized by high levels of proliferative, migratory and invasion activities as well as high resistance to treatment. These hallmarks typify the aggressive tumor phenotype and account for the very poor prognosis and as yet, the incurable nature of the disease. Chemotherapeutic agents are commonly administered orally or intravenously [9] These routes of administration do not provide high concentrations of drugs in the brain parenchyma especially because of the blood-brain barrier (BBB) that isolates the brain from the rest of the body [10]. There is a critical need to develop successful methods to safely open the BTB in order to improve chemotherapeutic treatment for malignant glioma
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