A sustained release antifibrotic prevents stricture formation in preclinical models of Crohn’s and other GI tract strictures

Introduction:: Fibrosis in the GI tract represents a leading cause of morbidity and mortality. In Crohn’s disease, more than one third of patients will experience stricture formation. Current treatment options include medical therapy to target inflammation, endoscopic dilation as well as surgery. Systemic anti-inflammatory therapies have a modest impact on the natural history of strictures. Surgery is effective, but anastomotic strictures oftentimes occur. Endoscopic dilation is safe and effective for short anastomotic strictures in the short term, but strictures also oftentimes recur. Currently, there are no effective therapies to specifically target the fibrosis process at the site of strictures. In this study, we aimed to develop a stricture therapeutic that (1) has high intrinsic anti-fibrotic properties, (2) can be delivered in a sustained fashion so that it can be (3) delivered topically at the time of endoscopic stricture dilation. Since wound healing following endoscopic stricture dilation is a process that takes days to weeks, we hypothesized that a sustained release antifibrotic has the potential of modulating healing processes, maintaining the lumen diameter, with the net result of decreased further endoscopic or surgical interventions.


Materials and Methods:: A high-throughput drug screening was performed to identify small molecules with antifibrotic properties. We found that sulconazole, an FDA approved anti-fungal has high intrinsic anti-fibrotic properties. Next, sulconazole was formulated as sustained released nanocrystals. Particle size, polydispersity index and surface charge were measured. In vitro drug release was characterized (Fig. 1). Two rodent fibrosis models (skin fibrosis model and intestine transplant model) as well as a newly established swine model of GI strictures were utilized to verify the therapeutic effect.


Results, Conclusions, and Discussions:: Result: We demonstrate, that the sustained release nanocrystal formulation of sulconazole (Sul-NC) is effective at reducing fibrosis in two relevant mouse fibrosis models. Most importantly, in a patient-like swine model of GI tract strictures, a single injection of Sul-NC after balloon dilation prevented re-stricturing as measured by a significant increase in the esophageal diameter compared to placebo (Fig. 2). Sulconazole was found to inhibit fibroblast proliferation as well as activation of myofibroblasts. Relevant genes, such as a-SMA, collagen-1, collagen-3 and others were inhibited.

Conclusions: Sul-NC is an effective anti-fibrotic in preclinical models of GI tract strictures. Further studies are needed for clinical translation.


Acknowledgements (Optional): : This work was financially supported by Crohn’s and Colitis Foundation Litwin IBD Pioneers program and the Helmsley Foundation

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