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Abstract Covalent attachment of thiols to the tyrosine residues of silk fibroin is accomplished with a high degree of functionalization through the reaction of a pyridyldithiol‐containing N‐hydroxysuccinimidal‐ester and an amino‐tyrosine silk intermediate. The extent of thiol modification is characterized by1H NMR and UV–vis spectroscopy. Further modification of the thiol groups is probed by reacting with an iodoacetamide‐containing small molecule resulting in a novel fluorescent silk derivative. Last, the ability of the thiolated silk to form hydrogels in situ is investigated.
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Local and Sustained Baricitinib Delivery to the Skin through Injectable Hydrogels Containing Reversible Thioimidate Adducts
Abstract Janus kinase (JAK) inhibitors are approved for many dermatologic disorders, but their use is limited by systemic toxicities including serious cardiovascular events and malignancy. To overcome these limitations, injectable hydrogels are engineered for the local and sustained delivery of baricitinib, a representative JAK inhibitor. Hydrogels are formed via disulfide crosslinking of thiolated hyaluronic acid macromers. Dynamic thioimidate bonds are introduced between the thiolated hyaluronic acid and nitrile‐containing baricitinib for drug tethering, which is confirmed with1H and13C nuclear magnetic resonance (NMR). Release of baricitinib is tunable over six weeks in vitro and active in inhibiting JAK signaling in a cell line containing a luciferase reporter reflecting interferon signaling. For in vivo activity, baricitinib hydrogels or controls are injected intradermally into an imiquimod‐induced mouse model of psoriasis. Imiquimod increases epidermal thickness in mice, which is unaffected when treated with baricitinib or hydrogel alone. Treatment with baricitinib hydrogels suppresses the increased epidermal thickness in mice treated with imiquimod, suggesting that the sustained and local release of baricitinib is important for a therapeutic outcome. This study is the first to utilize a thioimidate chemistry to deliver JAK inhibitors to the skin through injectable hydrogels, which has translational potential for treating inflammatory disorders.
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- Award ID(s):
- 2309043
- PAR ID:
- 10503354
- Publisher / Repository:
- Springer
- Date Published:
- Journal Name:
- Advanced Healthcare Materials
- ISSN:
- 2192-2640
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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- Free Publicly Accessible Full Text
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Accepted Manuscript
- Journal Article:
- https://doi.org/10.1002/adhm.202303256
