A Pro‐Regenerative Supramolecular Prodrug Protects Against and Repairs Colon Damage in Experimental Colitis
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) inhi...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2024-04-01
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| Series: | Advanced Science |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/advs.202304716 |
| _version_ | 1797227539050004480 |
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| author | Kelsey G. DeFrates Elaine Tong Jing Cheng Ellen Heber‐Katz Phillip B. Messersmith |
| author_facet | Kelsey G. DeFrates Elaine Tong Jing Cheng Ellen Heber‐Katz Phillip B. Messersmith |
| author_sort | Kelsey G. DeFrates |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-24T14:42:24Z |
| format | Article |
| id | doaj.art-0f671bc2f0e6463e9ae2f5f92b3f1e88 |
| institution | Directory Open Access Journal |
| issn | 2198-3844 |
| language | English |
| last_indexed | 2024-04-24T14:42:24Z |
| publishDate | 2024-04-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj.art-0f671bc2f0e6463e9ae2f5f92b3f1e882024-04-02T20:51:56ZengWileyAdvanced Science2198-38442024-04-011113n/an/a10.1002/advs.202304716A Pro‐Regenerative Supramolecular Prodrug Protects Against and Repairs Colon Damage in Experimental ColitisKelsey G. DeFrates0Elaine Tong1Jing Cheng2Ellen Heber‐Katz3Phillip B. Messersmith4Department of Bioengineering University of California, Berkeley Berkeley CA 94720 USADepartment of Bioengineering University of California, Berkeley Berkeley CA 94720 USADepartment of Bioengineering University of California, Berkeley Berkeley CA 94720 USALankenau Institute for Medical Research Wynnewood PA 19096 USADepartment of Bioengineering University of California, Berkeley Berkeley CA 94720 USAAbstract 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.https://doi.org/10.1002/advs.202304716HIF‐1αinflammatory bowel diseaseprolyl hydroxylase inhibitorregeneration |
| spellingShingle | Kelsey G. DeFrates Elaine Tong Jing Cheng Ellen Heber‐Katz Phillip B. Messersmith A Pro‐Regenerative Supramolecular Prodrug Protects Against and Repairs Colon Damage in Experimental Colitis Advanced Science HIF‐1α inflammatory bowel disease prolyl hydroxylase inhibitor regeneration |
| title | A Pro‐Regenerative Supramolecular Prodrug Protects Against and Repairs Colon Damage in Experimental Colitis |
| title_full | A Pro‐Regenerative Supramolecular Prodrug Protects Against and Repairs Colon Damage in Experimental Colitis |
| title_fullStr | A Pro‐Regenerative Supramolecular Prodrug Protects Against and Repairs Colon Damage in Experimental Colitis |
| title_full_unstemmed | A Pro‐Regenerative Supramolecular Prodrug Protects Against and Repairs Colon Damage in Experimental Colitis |
| title_short | A Pro‐Regenerative Supramolecular Prodrug Protects Against and Repairs Colon Damage in Experimental Colitis |
| title_sort | pro regenerative supramolecular prodrug protects against and repairs colon damage in experimental colitis |
| topic | HIF‐1α inflammatory bowel disease prolyl hydroxylase inhibitor regeneration |
| url | https://doi.org/10.1002/advs.202304716 |
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