Non-traditional and alternative medicines are becoming increasingly attractive approaches for the treatment of various diseases. Among the non-traditional approaches is the use of food derivatives, which have the advantage of being non-toxic. One such dietary ingredient is curcumin, which constitutes the yellow pigment of turmeric, the spice that gives yellow color to curry. Recent studies show that curcumin has both anti-inflammatory and anti-cancer properties. Carcinoembryonic antigen (CEA), a glycosylated protein secreted by tumor cells, has been implicated in the development of hepatic metastasis of human colorectal cancers. CEA binds to Kupffer cells, the resident macrophages in the liver, inducing the expression of cytokines, such as tumor necrosis factor alpha (TNF-alpha) and interleukin-1beta (IL-1beta). These, in turn, induce the expression of adhesion molecules on endothelial cells. Tumor cells expressing carbohydrate ligands to adhesion molecules have been reported to bind to hepatic endothelial cells, resulting in liver metastasis. Since curcumin is a potent inhibitor of cytokine synthesis in macrophages, it would be ideal to target curcumin to Kupffer cells to suppress the synthesis of pro-metastatic cytokines. However, curcumin is poorly absorbed from the gut, and hence, oral delivery is an inefficient way of targeting curcumin to specific cell types. Therefore, it is the objective of this proposal to develop a highly efficient liposome-based delivery system to specifically target curcumin to Kupffer cells/macrophages. A liposomal delivery system would provide a 200-fold improvement in targeting Kupffer cells compared to whole body distribution. Accordingly, in the first objective, curcumin-encapsulated liposomal formulations will be designed for in vivo delivery in experimental animals. Curcumin will be delivered using pH-sensitive liposomes, which are designed to destabilize the endosomal membrane, such that, following sequestration by Kupffer cells/macrophages, the liposomal contents will be released into the cytosol. It is expected that the liposomal formulation will deliver curcumin at least two orders of magnitude more efficiently to Kupffer cells than by oral administration. In the second objective, following a successful delivery of liposomal-curcumin, the in vivo efficacy of curcumin to suppress lipopolysaccharide (LPS)-induced production of cytokines and prostanoids will be tested. Further, the efficacy of curcumin to inhibit LPS-induced expression (mRNA) of adhesion molecules, ICAM-1 and E-selectin in endothelial cells will also be determined. In another series of experiments, liver slices and Kupffer cells from rats pre-injected with curcumin will be exposed to CEA and LPS separately, to assess the extent of inhibition of TNF-alpha and IL-1beta production by curcumin administration. A successful inhibition of cytokine and prostanoid secretions by liposomal-curcumin will greatly enhance our ability to discover new and non-toxic ways to treat cancer and other inflammatory diseases. These studies will provide valuable pre-clinical information on the in vivo potential of the liposomal-curcumin formulation to abrogate liver metastasis of colorectal cancer.
