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bioRxiv · 10.1101/2022.09.28.509483

Temperature-triggered in situ forming lipid mesophase gel for local treatment of ulcerative colitis

Carone, M.·Spalinger, M. R.·Gaultney, R. A.·Mookhoek, A.·Krebs, P.·Rogler, G.·Luciani, P.·Aleandri, S.
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Abstract

Ulcerative colitis (UC) is a chronic inflammatory bowel disease affecting the colonic mucosa. There is no cure for UC and its chronic relapsing/remitting nature strongly affects patient quality of life. Current treatment options frequently have significant side effects and remission rates are limited raising a demand for new treatment strategies. Novel therapeutic approaches that could maximize the drug concentration at the site of inflammation with minimal systemic exposure, like topical applications, would address this unmet clinical need. To date, few drug delivery systems (DDSs) have been designed to topically convey small molecules to the rectum and left-sided colon. Here, we developed and tested a drug delivery platform for topical treatment of UC based on a temperature-triggered in situ forming adhesive lipid gel (TIF-Gel). Due to its soft, gel-like consistency, its high encapsulation efficacy, and its drug-controlled release, TIF-Gel suggests a more patient-friendly and effective application with respect to the rectal formulations currently available. Capitalizing on the biocompatible and biodegradable self-assembled structure of lipid mesophases (LMPs), we loaded TIF-Gel with tofacitinib (TOFA; a hydrophilic inhibitor of the enzymes Janus kinase 1 and 3) or TAC (a hydrophobic immunosuppressive drug), both of which are indicated in the treatment of UC. We designed and fully characterized our biocompatible lipid formulation in vitro and tested it in vivo using two different murine models of inflammatory bowel disease: chemically-induced and T cell transfer-mediated. Both approaches (TIF-Gel-TOFA and TIF-Gel-TAC) led to reductions in colitis disease severity and intestinal inflammation compared to vehicles, therefore showing therapeutic efficacy. Overall, our findings show that TIF-Gel can deliver drugs locally to the colonic mucosa to mitigate intestinal inflammatory disease in a pre-clinical model. They also suggest that, in a clinical setting, TIF-Gel might provide a patient-friendly approach to improve colitis while allowing for a reduction of the adverse effects associated with a systemic therapy.

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Carone, M., Spalinger, M. R., Gaultney, R. A., Mookhoek, A., Krebs, P., Rogler, G., Luciani, P., Aleandri, S.. 2022-09-30. Temperature-triggered in situ forming lipid mesophase gel for local treatment of ulcerative colitis. https://doi.org/10.1101/2022.09.28.509483

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