1. A Pro-Regenerative Supramolecular Prodrug Protects Against and Repairs Colon Damage in Experimental Colitis.
- Author
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DeFrates, Kelsey, Tong, Elaine, Cheng, Jing, Heber-Katz, Ellen, and Messersmith, Phillip
- Subjects
HIF‐1α ,inflammatory bowel disease ,prolyl hydroxylase inhibitor ,regeneration ,Mice ,Animals ,Colitis ,Inflammatory Bowel Diseases ,Intestinal Mucosa ,Disease Models ,Animal ,Mammals - Abstract
Structural repair of the intestinal epithelium is strongly correlated with disease remission in inflammatory bowel disease (IBD); however, ulcer healing is not addressed by existing therapies. To address this need, this study reports the use of a small molecule prolyl hydroxylase (PHD) inhibitor (DPCA) to upregulate hypoxia-inducible factor one-alpha (HIF-1α) and induce mammalian regeneration. Sustained delivery of DPCA is achieved through subcutaneous injections of a supramolecular hydrogel, formed through the self-assembly of PEG-DPCA conjugates. Pre-treatment of mice with PEG-DPCA is shown to protect mice from epithelial erosion and symptoms of dextran sodium sulfate (DSS)-induced colitis. Surprisingly, a single subcutaneous dose of PEG-DPCA, administered after disease onset, leads to accelerated weight gain and complete restoration of healthy tissue architecture in colitic mice. Rapid DPCA-induced restoration of the intestinal barrier is likely orchestrated by increased expression of HIF-1α and associated targets leading to an epithelial-to-mesenchymal transition. Further investigation of DPCA as a potential adjunctive or stand-alone restorative treatment to combat active IBD is warranted.
- Published
- 2024