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 with 1H and 13C 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.
Subject(s)
Azetidines , Hydrogels , Purines , Pyrazoles , Skin , Sulfonamides , Animals , Hydrogels/chemistry , Purines/chemistry , Purines/pharmacology , Sulfonamides/chemistry , Sulfonamides/pharmacology , Sulfonamides/administration & dosage , Mice , Pyrazoles/chemistry , Pyrazoles/pharmacology , Azetidines/chemistry , Azetidines/pharmacology , Skin/drug effects , Skin/metabolism , Skin/pathology , Humans , Psoriasis/drug therapy , Psoriasis/pathology , Psoriasis/chemically induced , Imiquimod/chemistry , Imiquimod/pharmacology , Janus Kinase Inhibitors/chemistry , Janus Kinase Inhibitors/pharmacology , FemaleABSTRACT
This case describes a patient with known mantle cell lymphoma without cutaneous involvement presenting with a diffuse morbilliform rash during an inpatient admission for bacterial pneumonia. The patient was thought to have a hypersensitivity to antibiotics but failed to improve after the offending agents were stopped. A skin biopsy revealed metastatic cutaneous mantle cell lymphoma. Treatment with high-dose corticosteroids and chemotherapy was initiated resulting in the resolution of the rash.
