Local enema treatment to inhibit FOLH1/GCPII as a novel therapy for inflammatory bowel disease

Publication date: Available online 31 January 2017
Source:Journal of Controlled Release
Author(s): Abhijit A. Date, Rana Rais, Taarika Babu, Jairo Ortiz, Pranjali Kanvinde, Ajit G. Thomas, Sarah C. Zimmermann, Alexandra J. Gadiano, Gilad Halpert, Barbara S. Slusher, Laura M. Ensign
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 30min 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 24h 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.

Graphical abstract

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