Targeting of therapeutics to diseased intestinal tissue in inflammatory bowel disease.

Current therapies for inflammatory bowel disease (IBD) fail to address disease pathogenesis, providing only symptomatic alleviation, and lack organ specificity, with most of the drug reaching the systemic circulation rather than being targeted locally to the diseased intestine. The objective of this research project was to study two novel approaches to IBD therapy; adenoviral gene delivery and local liposomal drug delivery after intralumenal administration. Caco-2 cells in in vitro models of mucosal wound healing, ex vivo intestinal biopsy cultures and an in vitro M-cell model were employed to study interactions of adenoviral vectors and intestinal epithelium. Transgene expression was quantified by biophotonic imaging. The rat was used as an animal model for investigation of intestinal absorption and metabolism of the model compound, 6-mercaptopurine, administered in solution or as a liposomal formulation, coupled with HPLC and liquid scintillation counting bioanalytical methods. It was determined that restituting intestinal epithelial cells are transfected much more efficiently by adenoviral vectors than their healthy, confluent counterparts. The effect appears to be related to integrin and CAR expression by the restituting cells, associated with the migration process. Significant differences in adenoviral transduction of Caco-2 cells and M-cells compared to other epithelia cell types were observed. Liposomal formulation of 6-mercaptopurine, despite mucosal adherence, did not prove advantageous in terms of local delivery compared to solution. This is in contrast to previous studies with a 5-aminosalicylic acid liposomal formulation. The differences can be explained by the different physicochemical properties and absorption characteristics of the two drugs. This study suggests that gastrointestinal epithelium, in disorders such as IBD where epithelial restitution takes place, represents a valid target for gene transfer. As gastrointestinal gene delivery is still in its infancy, liposomal formulations that offer an increased drug residence time at the inflamed intestinal tissue due to mucosal adherence are an attractive alternative to traditionally used controlled/delayed release formulations of small drug molecules. However, drug physicochemical properties and intestinal absorption characteristics will dictate the potential for these formulations.PhDHealth and Environmental SciencesPharmaceutical sciencesUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/124708/2/3150234.pd