Local and Sustained Baricitinib Delivery to the Skin Through Injectable Hydrogels Containing Reversible Thioimidate Adducts.

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 were engineered for the local and sustained delivery of baricitinib, a representative JAK inhibitor. Hydrogels were formed via disulfide crosslinking of thiolated hyaluronic acid macromers. Dynamic thioimidate bonds were introduced between the thiolated hyaluronic acid and nitrile-containing baricitinib for drug tethering, which was confirmed with 1 H and 13 C nuclear magnetic resonance (NMR). Release of baricitinib was 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 were injected intradermally into an imiquimod-induced mouse model of psoriasis. Imiquimod increased epidermal thickness in mice, which was unaffected when treated with baricitinib or hydrogel alone. Treatment with baricitinib hydrogels suppressed the increased epidermal thickness in mice treated with imiquimod, suggesting that the sustained and local release of baricitinib was 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. This article is protected by copyright. All rights reserved.