(L-441) Transformative therapy of acute colitis with programmable micelles

Introduction:: Ulcerative colitis is a chronic condition that is contributed by a dysregulated immune response, and a complex interplay between genetic, microbial, and environmental factors leading to acute intestinal inflammation of the colon and rectum.  Intravenous corticosteroids are the first-line treatment for UC.  Yet a large subset of patients are resistant to this regimen and require aggressive therapies with immunomodulators, which often present toxic side-effects and ultimately lead to other comorbidities.  Therefore, a significant clinical need exists for novel treatments that will reduce intestinal inflammation with minimal systemic toxicities, and improve the diversity of beneficial gut microbiome for a sustained long-term anti-inflammatory response. 

Materials and Methods:: In this work we demonstrate a new paradigm in colitis treatment by designing programmable micelles with biopolymers already in human use and loaded with an inhibitor of the stimulator of interferon genes (STING) pathway. Emerging evidence now strongly supports cGAS-mediated STING signaling as a mechanism that exacerbates acute colitis in both mouse models and in patients.  Yet not a single cGAS/STING inhibitor is clinically approved for treatment in IBDs patients in part due to poor pharmacokinetics of these drugs after oral gavage resulting in rapid clearance before therapeutic benefit, and limited targeting ability in vivo resulting in severe toxicities. 

Results, Conclusions, and Discussions::

Our programmable micelles not only improves the bioavailability of the hydrophobic STING inhibitor by encapsulating in the micellar cavity, but also targets the inflammatory colonic mucosa and proinflammatory macrophages.  The micelles are designed to trigger drug release primarily at the site of inflammation reducing off-target systemic effects. Our results demonstrate that treatment with programmable micelles enhanced bodyweight recovery associated with DSS-induced acute colitis in mice and maintained colon length, and micelle therapy reduced pro-inflammatory cytokines and attenuated STING expression in colon.  We envision that these therapeutic micelles will ultimately be an advanced drug delivery vehicle for universal encapsulation of a number of hydrophobic drugs that have poor pharmacokinetics in vivo and implement in other subsets of IBDs (chronic colitis, Chron’s disease) and other disorders (neurodegeneration) linked to the STING pathway.

Acknowledgements (Optional): : We acknowledge CDMRP award HT9425-23-1-0071.

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