Abstract
Here we evaluate the potential for local administration of a small molecule FOLH1/GCPII inhibitor 2-phosphonomethyl pentanedioic acid (2-PMPA) as a novel treatment for inflammatory bowel disease (IBD). We found that FOLH1/GCPII enzyme activity was increased in the colorectal tissues of mice with TNBS-induced colitis, and confirmed that 2-PMPA inhibited FOLH1/GCPII enzyme activity ex vivo. In order to maximize local enema delivery of 2-PMPA, we studied the effect of vehicle tonicity on the absorption of 2-PMPA in the colon. Local administration of 2-PMPA in a hypotonic enema vehicle resulted in increased colorectal tissue absorption at 30 min compared to 2-PMPA administered in an isotonic enema vehicle. Furthermore, local delivery of 2-PMPA in hypotonic enema vehicle resulted in prolonged drug concentrations for at least 24 h with minimal systemic exposure. Finally, daily treatment with the hypotonic 2-PMPA enema ameliorated macroscopic and microscopic symptoms of IBD in the TNBS-induced colitis mouse model, indicating the potential of FOLH1/GCPII inhibitors for the local treatment of IBD.
Original language | English (US) |
---|---|
Pages (from-to) | 132-138 |
Number of pages | 7 |
Journal | Journal of Controlled Release |
Volume | 263 |
DOIs | |
State | Published - Oct 10 2017 |
Keywords
- 2-PMPA
- Colitis
- Folate polyglutamate
- Hypotonic
- N-acetyl-aspartyl glutamate
- TNBS
ASJC Scopus subject areas
- Pharmaceutical Science