Inflammatory Bowel Disease (IBD) is a debilitating disease that affects ~70,000 new people every year in the USA. Additionally, IBD increases the risk of developing colon cancer. Due to the chronicity of the disease and inconsistent treatment outcomes of current anti-IBD drugs (e.g. ~30% non-responders to anti-TNFα agents), and related deadly side effects (such as sepsis), the majority of IBD patients (in millions) turn to complementary and alternative medicines (CAMs). Thus, it is imperative that in addition to the pursuit of “safe precision medicine”, there is an unmet need to advance safe CAMs with strong anti-inflammatory properties. In this regard, the anti-inflammatory role of the safe dietary component curcumin is widely recognized due to its multiple targets in the inflammation pathways, which may be beneficial in managing the inflammatory flares induced by a wide range of mechanisms in IBD that may include non-responders to precision medicine. Recently, the enthusiasm for curcumin has been diminished due to its failure in several clinical trials for other diseases, mainly due to its poor bioavailability. Improving the curcumin bioavailability consistently for clinical advancement has been challenging because of its very high metabolic rate. In contrast to existing strategies, our working hypothesis is by delivering soluble and bioactive curcumin locally to the inflammation site (without systemic exposure), the road-blocks could be circumvented in advancing curcumin for long-term complementary therapy for IBD and associated cancer. To this end, a uniquely engineered polymer-based technology, Ora-Curcumin-S (OC-S), was invented by molecular complexation of curcumin with a group of polymers called Eudragits®. Strong published preliminary data showed that OC-S is >2000 times water- soluble than curcumin and delivered high proportions of soluble curcumin to the colon lumen without detectable absorption in both healthy and colitis mice. Further, it inhibited TLR4 activity on immune cells, which interferes with multiple pathways related to immune dysregulation in IBD and epithelial transition to cancer. Importantly, OC-S effectively inhibited colitis-associated immune deregulations and mucosal injury in a mouse model of colitis at doses 3-60 times lower than reported curcumin studies. The OC-S complexes are the first reported colon-targeted curcumin delivery systems that are highly soluble and stable in water. Therefore, OC-S, for the first time, will enable us to test curcumin for local therapy for IBD. The overall goal of this proposal is to perform a thorough preclinical evaluation and examine the cellular mechanisms of inflammation-targeted OC- S complexes in inhibiting the ulcerative colitis (UC). The specific aims of the proposal include 1) To establish the safety and targeted delivery of OC-S to the inflamed colon, 2) To identify specific molecular/cellular functions ameliorated by the OC-S for its anti-colitis activity. We anticipate proposed studies to provide a conclusive outcome and support the decision for future clinical evaluation of OC-S as a local therapy to reduce IBD severity and associated cancer.

As there is no cure for inflammatory bowel disease (IBD), to alter the clinical management of IBD, intervention should ideally start at an early stage or before potential remission (in patients). Since new drug discovery is time-consuming and expensive, we repurposed the safe dietary component curcumin with uniquely designed colon-targeted anti-inflammatory polymer complexes. The overall goal of this proposal is to perform a thorough preclinical evaluation and examine the cellular mechanisms of the inflammation-targeted polymer-curcumin complexes in inhibiting the ulcerative colitis.