Murtaza Tambuwala
University of Ulster, Northern Ireland.
Title: Colon targeted delivery of the hydroxylase inhibitor dimethyloxallogylcine (DMOG) provides enhanced protection in a murine model of colitis
Biography
Biography: Murtaza Tambuwala
Abstract
Pharmacologic hydroxylase inhibition represents a potentially important new therapeutic approach to colitis. However, because of potential side effects associated with systemic delivery of hydroxylase inhibitors including unwanted regulation of angiogenic, metabolic and erythropoeitic processes, it is desirable to develop new methods of delivery of such compounds to specific regions of the intestine in order to provide local therapeutic effects without systemic exposure. We have utilised an emulsion-based drug delivery system to attempt to achieve this goal. Initially, we demonstrated that the formulation of the hydroxylase inhibitor DMOG into a novel emulsion-based colon-specific delivery system was without effect upon the biological activity of the drug. The physical process of formulation of DMOG into the colon-specific drug delivery sphere system does not impact upon it’s biological activity. We next investigated the whether formulated DMOG is delivered specifically to the colon when the beads are administered orally to mice. This was investigated by using transgenic mice which ubiquitously express the firefly luciferase gene under the control of a concatomer of NF-kappaB response elements (NRE) to assess NF-kappaB activity in vivo. Our results demonstrate that colon-targeted DMOG delivery resulted in an effective and selective elevation in basal NF-kappaB activity in the colon. We next investigated whether the therapeutic efficacy of colon-specific DMOG delivery in a murine model of DSS-induced colitis. Results from these experiments suggest that colon targeted DMOG bead are protective against experimental colitis in mice at a 40 fold lower dose as compared to systemic administration of DMOG. Our previous work has demonstrated that a significant proportion of the protective effects of DMOG observed in models of intestinal inflammation is a result of enhanced intestinal epithelial barrier function which diminishes the exposure of the mucosal immune system to luminal antigenic material. We also investigated the impact of colon-targeted DMOG delivery on intestinal barrier function in mice exposed to DSS with and without DMOG along with an oral gavage of 4kD FITC labelled dextran. The colon-targeted DMOG provided an approximately equivalent degree of protection to intestinal epithelial barrier function while the non-colon targeted DMOG did not significantly decrease DSS-induced intestinal barrier dysfunction. In summary, these data demonstrate that formulation of hydroxylase inhibitors in a colontargeted manner allows a retention of therapeutic efficacy while significantly reducing systemic exposure and the potential for associated unwanted side effects.