Developing polymer-drug complex based toll-like receptor (TLR-2/TLR-4) antagonist for modulating gut innate immune system to prevent/treat IBD and colon cancer

Abstract

Abstract Continuous inflammation in the colon often leads to chronic diseases such as inflammatory bowel disease (IBD) and colorectal cancer. Recent evidence strongly suggests the role of Toll-Like Receptors 2 and 4 in the etiology of aforementioned diseases. Therefore, pharmacological inhibition of TLR-2/TLR-4 has been a new promising strategy for preventing inflammation in IBD and colorectal cancer. In the current study, we have developed a novel polymer-drug complex (Ora-Curcumin) as a TLR-2/TLR-4 antagonist to modulate the gut innate immune system. Ora-Curcumin is a molecular complex of curcumin with a hydrophilic polymer Eudrgit® S100 prepared by nano-precipitation. Ora-curcumin is more water soluble (~1000 times) and stable than curcumin in aqueous buffers. It is water soluble only at pHs above 6.8. Therefore, once consumed orally, it is expected to be soluble and functionally available only at the luminal side of the colon where the pH reaches 6.8. In addition, Ora-Curcumin was potent TLR-4 antagonist that significantly inhibited the release of IL-8 and TNF-a from TLR-4 expressing human kidney epithelial cells (HEK293TLR4YFP-MD2) and mouse dendritic cells, respectively, in response to TLR stimulation with Monophosphoryl Lipid A (MPLA) or dead E. coli. The in-vivo potential of Ora-Curcumin in modulation of acute inflammation and intestinal microbiome is currently in progress. To this end, we have developed a unique polymer based water soluble TLR-2/TLR-4 antagonist which also provides enhanced local delivery to colon to prevent or treat IBD and colorectal cancer. As an anti-bacterial and by altering host immune system to control inflammation, Ora-Curcumin is also expected to modulate colon microbiome and improve GI health.