Pharmacological Modulation of Blood–Brain Barrier Permeability by Kinin Analogs in Normal and Pathologic Conditions

The blood–brain barrier (BBB) is a major obstacle to the development of effective diagnostics and therapeutics for brain cancers and other central nervous system diseases. Peptide agonist analogs of kinin B1 and B2 receptors, acting as BBB permeabilizers, have been utilized to overcome this barrier....

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Bibliographic Details
Published in:Pharmaceuticals (Basel, Switzerland) Switzerland), 2020-09, Vol.13 (10), p.279
Main Authors: Sikpa, Dina, Whittingstall, Lisa, Savard, Martin, Lebel, Réjean, Côté, Jérôme, McManus, Stephen, Chemtob, Sylvain, tin, David, Lepage, Martin, Gobeil, Fernand
Format: Article
Language:English
Subjects:
blood–brain barrier permeability
Brain cancer
Cancer therapies
chemotherapy
CNS diseases
Drug delivery systems
Drugs
G protein-coupled receptors
kinin analogs
Microscopy
Peptides
Permeability
radiotherapy
Regulatory approval
Tumors
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Summary:The blood–brain barrier (BBB) is a major obstacle to the development of effective diagnostics and therapeutics for brain cancers and other central nervous system diseases. Peptide agonist analogs of kinin B1 and B2 receptors, acting as BBB permeabilizers, have been utilized to overcome this barrier. The purpose of the study was to provide new insights for the potential utility of kinin analogs as brain drug delivery adjuvants. In vivo imaging studies were conducted in various animal models (primary/secondary brain cancers, late radiation-induced brain injury) to quantify BBB permeability in response to kinin agonist administrations. Results showed that kinin B1 (B1R) and B2 receptors (B2R) agonists increase the BBB penetration of chemotherapeutic doxorubicin to glioma sites, with additive effects when applied in combination. B2R agonist also enabled extravasation of high-molecular-weight fluorescent dextrans (155 kDa and 2 MDa) in brains of normal mice. Moreover, a systemic single dose of B2R agonist did not increase the incidence of metastatic brain tumors originating from circulating breast cancer cells. Lastly, B2R agonist promoted the selective delivery of co-injected diagnostic MRI agent Magnevist in irradiated brain areas, depicting increased vascular B2R expression. Altogether, our findings suggest additional evidence for using kinin analogs to facilitate specific access of drugs to the brain.
ISSN:1424-8247
1424-8247
DOI:10.3390/ph13100279