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

Dina Sikpa,David Fortin,Martin Lepage,Lisa Whittingstall,Sylvain Chemtob,Fernand Gobeil,Martin Savard,Stephen Mcmanus,Jérôme Côté,Réjean Lebel

doi:10.3390/ph13100279

Abstract

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.

Highlights

A major issue in treating brain cancers and other central nervous system (CNS) diseases is drug access to specific areas of the brain
For drug delivery to brain cancers, osmotic blood–brain barrier (BBB) disruption with mannitol is the only effective method that has successfully made its way into the clinic, with nine International BBB-Consortium Centers operating across the United States, Israel, and Canada, including in our Centre hospitalier universitaire de Sherbrooke (CHUS, Québec, Canada) [6–8]
As it is known that B2 receptors (B2R) is mostly coupled to the Gαq pathway, the functional assays consisted of testing the ability of BK and its analogs to stimulate the inositol monophosphate (IP) cascade by measuring IP1 accumulation over 30 min

Summary

Introduction

A major issue in treating brain cancers and other central nervous system (CNS) diseases is drug access to specific areas of the brain. For drug delivery to brain cancers, osmotic BBB disruption with mannitol is the only effective method that has successfully made its way into the clinic, with nine International BBB-Consortium Centers operating across the United States, Israel, and Canada, including in our Centre hospitalier universitaire de Sherbrooke (CHUS, Québec, Canada) [6–8]. Duly approved, it remains highly invasive, requires general anesthesia, and is accompanied by the nonselective delivery of anticancer drugs to normal brain tissues, and is not compatible with chemotherapeutics that are neurotoxic (e.g., taxanes and cisplatin) [9]

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