Targeted delivery of the hydroxylase inhibitor DMOG provides enhanced efficacy with reduced systemic exposure in a murine model of colitis.

Abstract

Targeting hypoxia-sensitive pathways has recently been proposed as a new therapeutic approach to the treatment of intestinal inflammation. HIF-hydroxylases are enzymes which confer hypoxic-sensitivity upon the hypoxia-inducible factor (HIF), a major regulator of the adaptive response to hypoxia. Previous studies have shown that systemic (intraperitoneal) administration of hydroxylase inhibitors such as dimethyloxalylglycine (DMOG) is profoundly protective in multiple models of colitis, however the therapeutic potential of this approach is limited due to potential side-effects associated with systemic drug exposure and the fact that orally delivered DMOG is ineffective (likely due to drug inactivation by gastric acid). In order to overcome these issues, we formulated DMOG in a liquid emulsion drug delivery system which, when coated with specific polymer coatings, permits oral delivery of a reduced dose which is released locally throughout the colon. This colon-targeted DMOG formulation demonstrated increased relative colonic bioactivity with reduced systemic exposure and provided a similar degree of protection to systemic (intraperitoneal) administration at a 40-fold lower dose in DSS-induced colitis. In summary, targeted delivery of DMOG to the colon provides local protection resulting in enhanced efficacy with reduced systemic exposure in the treatment of colitis. This novel approach to targeting hydroxylase inhibitors to specific diseased regions of the GI tract may improve it's potential as a new therapeutic in inflammatory bowel diseases such as ulcerative colitis.

• Authors: Murtaza M Tambuwala, Mario C Manresa, Eoin P Cummins, Vincenzo Aversa, Ivan S Coulter, Cormac T Taylor
• Journal: Journal of controlled release : official journal of the Controlled Release Society (J Control Release) Vol. 217 Pg. 221-7 (Nov 10 2015) ISSN: 1873-4995 [Electronic] Netherlands
• PMID: 26385165 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier B.V. All rights reserved.

Chemical References

• Amino Acids, Dicarboxylic
• NF-kappa B
• Dextran Sulfate
• Mixed Function Oxygenases
• Luciferases, Firefly
• oxalylglycine

Topics

• Administration, Oral
• Amino Acids, Dicarboxylic (administration & dosage, therapeutic use)
• Animals
• Colitis (chemically induced, drug therapy)
• Colon (metabolism)
• Dextran Sulfate
• Disease Models, Animal
• Drug Delivery Systems
• Female
• HeLa Cells
• Humans
• Luciferases, Firefly (genetics, metabolism)
• Mice
• Mice, Transgenic
• Mixed Function Oxygenases (antagonists & inhibitors)
• NF-kappa B (metabolism)
• Treatment Outcome