Curcumin, a natural polyphenolic compound, is the major active constituent isolated from the rhizome of turmeric (curcuma longa Linn), a member of the ginger family (Zingiberaceae). Curcumin is a potent anti- inflammatory molecule that may interact with multiple molecular targets involved in inflammatory pathways. It has been suggested that curcumin could have therapeutic potential to treat inflammatory diseases, including inflammatory bowel disease (IBD). However, curcumin exhibits poor bioavailability because of its limited aqueous solubility, susceptibility to photo degradation, chemical instability, rapid metabolism, and short half- life. Efforts to develop new curcumin-based therapeutic approaches against IBD must overcome these challenges intrinsic to the properties of the curcumin molecule. My sponsor?s laboratory and other groups have recently demonstrated that artificially synthesized nanoparticles may be used to enhance the biological effects of incorporated drugs by protecting these drugs, including curcumin, from enzymatic degradation, providing controlled release and limiting nonspecific uptake by off-target tissues. However, nanoparticles synthesized to date have two major limitations: i) the requirement that each constituent of the synthesized nanoparticle be examined for potential in vivo toxicity before clinical application, and ii) their limited production scale. The use of nanoparticles derived from natural sources may overcome these limitations of synthetic nanoparticles. Here, I provide preliminary data on the characterization and efficient colon-targeting of nanoparticles derived from edible turmeric. In addition, I have demonstrated that a specific population of turmeric-derived nanoparticles (TDNPs), namely TDNP2, contains a high concentration of curcumin that is protected from degradation by the nanoparticle. In addition, I have demonstrated that orally administered TDNP2s target the colon and reduce acute intestinal inflammation. The central hypothesis of this proposal is that TDNP2s, naturally loaded with curcumin, may be a novel treatment for IBD.
In Aim 1, I will examine the treatment efficacy of TDNP2s in several distinct and well-established mouse models of IBD, including dextran sulfate sodium (DSS)-treated and IL10-/- and T/RAG-/- mice. I will also investigate intestinal cellular targets of TDNP2s and resulting intestinal cellular responses.
In Aim 2, I will use knockout (KO) and knock-in (KI) strategies to investigate whether curcumin is responsible for the intestinal anti-inflammatory effects of curcumin-loaded TDNP2s. This study represents proof of principle of a novel, natural, nontoxic delivery system that targets the inflamed intestinal mucosa and may easily be developed for large-scale production aimed at the treatment of IBD.
Factors implicated in the pathophysiology of intestinal inflammation include defects in intestinal epithelial barrier function, abnormal immune responses, and activities of the gut microbiota. Current agents used to treat human IBD have serious side effects, and in addition, most of these treatments target the damaging factors while not providing pro-healing factors that repair the damaged intestine. In the present study, we will examine a proof of principle for a novel natural, nontoxic delivery system, which targets the inflamed intestinal mucosa, blocks damaging factors while promoting pro-healing factors and could easily be developed for large-scale production aimed at the treatment of IBD.