Ulcer-Targeting Prodrug Particles to Promote Regenerative Healing in Inflammatory Bowel Disease

The current standard of treatment for inflammatory bowel disease (IBD), including ulcerative colitis and Crohn’s disease, is to reduce idiopathic intestinal inflammation with anti-inflammatory, immunosuppressant, and biologic drugs. However, there is a critical need for therapeutics that specifically address ulcer healing. Intestinal ulcers cause pain and intestinal dysfunction during disease flare ups, and chronic recurrence of mucosal and submucosal intestinal tissue damage can lead to fibrotic stenosis, stricture, and blockages. Ultimately, pathological ulcer healing leads 50-80% of Crohn’s and 10-30% of ulcerative colitis patients to require invasive bowel resection surgery within their lifetimes.<br/><br/>To address this need, we present a therapeutic prodrug particle containing the small molecule PHD inhibitor 1,4-dihydrophenanthrolin-4-one-3-carboxylic acid (DPCA), which has been shown to induce epimorphic-like regeneration in various mammalian tissues <i>in vivo</i>. This regeneration is the result of stabilization of transcription factor hypoxia-inducible factor 1α (HIF-1α), which mediates many downstream cellular processes critical to inflammation management and wound healing. DPCA was modified to assemble into ulcer-targeting prodrug particles, which show good biocompatibility and HIF-1α stabilization <i>in vitro</i>. Furthermore, oral administration of the particles <i>in vivo</i> showed protective effects on mouse weight and tissue architecture in a dextran sodium sulfate (DSS)-induced model of murine colitis. Mice treated with the particles also showed improved gut barrier function and regulation of immune response in colonic tissue. This prodrug particle represents a promising new platform to address the outstanding goals of preventing fibrosis and inducing histological healing in IBD.