Abstract 2803: Oral administration of an acid stable liposomal formulation of docosahexaenoic acid (DHA) delivers DHA and its LOX-metabolites to the circulation and the breast tissue of sprague dawley rats

Abstract

Abstract We have shown that dietary ratios of omega-3 to omega-6 fatty acids that significantly inhibited chemically-induced mammary carcinogenesis in the rat were in excess of 10:1 suggesting that a particular omega-3 fatty acid or its metabolite may account for the chemopreventive effects of such high ratios. Docosahexaenoic acid (DHA; 22:6 n-3), a component in fish oil, has been shown to inhibit mammary cancer-induced by chemical carcinogens (7,12-dimethylbenz-[a]-anthracene and N-methyl-N-nitrosourea) in the rat. The Western Diet in humans, with a ratio of 1:15 omega-3:omega-6 fatty acids, is not sufficient to provide the levels of DHA required for cancer prevention. Furthermore, mammals can't synthesize this fatty acid. Previously, a liposomal formulation for DHA for intravenous administration has been developed, but this route of administration is not appropriate for chemoprevention. Oral delivery for long term is the preferred approach. Therefore, we hypothesize that the oral delivery of a liposomal formulation of DHA which is resistant to oxidation and low gastric pH will enhance its bioavailability in the circulation and the breast tissues, and thus enhance the chemopreventive efficacy. We have developed for the first time an acid stable liposomal delivery system of DHA; average size determined by Dynamic Light Scattering is approximately 135nm, while that of the ghost formulation is approximately 150nm. This size is ideal for oral administration and can cross the enterocytes of the intestine. In a pilot study a single dose of liposomal DHA(1.54mg DHA/rat) was orally administered to female Sprague Dawley rats 21 days of age; rats were sacrificed after 24 hours by CO2 asphyxiation and their plasma and various organs including the breast tissue were harvested. The amount of DHA in the plasma and breast tissue was determined by gas chromatography flame ionization detection. Approximately 3.4% of the dose was determined to be in the plasma, while levels of DHA that reached the breast tissue were at least 5-fold higher than those measured in plasma. Using LC-MS/MS we detected DHA and its metabolites, 14-hydroxy DHA and 17-hydroxy DHA, catalyzed by LOX enzymes in rat plasma. In the breast tissue 4-hydroxy DHA, 14-hydroxy DHA, 17-hydroxy DHA, and 20-hydroxy DHA were detected. In summary, we report for the first time the detection of DHA and its LOX-metabolites in the circulation and breast tissue following the oral administration of liposomal DHA, suggesting that our nanotechnology-based approach is a promising strategy for breast cancer prevention. (Support: Institutional Funding) Citation Format: Christine G. Skibinski, Arunangshu Das, Kun-Ming Chen, Neil Trushin, Bogdan Prokopczyk, Cesar Aliaga, Mark Kester, Andrea Manni, Karam El-Bayoumy. Oral administration of an acid stable liposomal formulation of docosahexaenoic acid (DHA) delivers DHA and its LOX-metabolites to the circulation and the breast tissue of sprague dawley rats. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2803. doi:10.1158/1538-7445.AM2015-2803