B95

Curcumin is the active constituent of turmeric (Curcuma longa rhizomes), and has been shown to possess anti-inflammatory, anti-oxidant and anti-tumor properties. Recent studies have found that curcumin has a dose-dependent chemopreventive effect in several animal tumor bioassay systems including colon, duodenal, stomach, esophageal and oral carcinogenesis. The molecular basis of anti-carcinogenic and chemopreventive effects of curcumin is attributed to its effect on transcription factors like nuclear factor-κB (NF-κB) and activator protein-1 (AP-1), and other factors like growth regulators, adhesion molecules, apoptotic genes, angiogenesis regulators and cellular signaling molecules. In spite of its promising therapeutic index, the biological activity of curcumin is severely limited due to its poor bioavailability. Here, we aimed to enhance targeted delivery of curcumin for prostate cancer treatment by incorporating it into the liposomes (nanodelivery vehicles primarily composed of phospholipids) coated with prostate membrane specific antigen specific antibodies. We prepared curcumin-loaded liposomes of various lipid compositions by sonication at an average size of 100-150 nm. Un-entrapped curcumin was removed by size exclusion chromatography. We report that curcumin preferentially partitioned into liposomes prepared from dimyristoyl phosphatidyl choline (DMPC) and cholesterol among the various compositions tested. Liposome-entrapped curcumin was determined using a colorimetric assay at 450 nm. The mole ratio of liposomal lipid/curcumin was approximately 7:1 in DMPC/cholesterol liposomes. The anti-proliferative activity of liposomal curcumin was studied using two human prostate cancer cell lines (LNCaP and C42B) by a tetrazolium dye-based (MTT) assay. We report that treatment of cells with liposomal curcumin (5-10 μM) for 24-48 hours at 37oC resulted in at least 70-80% inhibition of cellular proliferation without affecting their viability. On the other hand, free curcumin exhibited similar inhibition only at 10-fold higher doses (> 50 μM). Control liposomes did not show any non-specific toxic effects at similar doses in our experiments. We also observed that LNCaP cells were relatively more sensitive to liposomal curcumin mediated block of cellular proliferation than C42B cells. We are currently developing liposome formulations with targeting ability to further improve efficacy of curcumin in vivo. Studies are also underway to elucidate the molecular mechanism(s) of chemopreventive potential of curcumin in prostate cancer.

[Fifth AACR International Conference on Frontiers in Cancer Prevention Research, Nov 12-15, 2006]