Liposome-Incorporated 3′,5′-O-Dipalmitoyl-5 -Fluoro-2′-Deoxyuridine as a Slow-Release Anti-Tumor Drug Depot in Rat Liver Macrophages

We synthesized the 3′,5′-O-dipalmitoyl derivative of 5-fluoro-6-[³H]-2′-deoxyuridine and incorporated it into the bilayers of multilamellar liposomes (400 nm diameter) of various lipid compositions. The prodrug-containing liposomes were incubated with rat liver macrophages (Kupffer cells) in monolayer culture and with lysosomal fractions from whole rat liver homogenates. The release of water-soluble radioactive degradation products from the cells was measured and we found the rate of release strongly dependent on the lipid composition of the liposomes. After 4 hours of incubation the release of radioactivity was 9-fold higher from egg-phosphatidylcholine / phosphatidylserine/cholesterol liposomes than from distearoylphosphatidylcholine / dipalmitoylphosphatidylglycerol/cholesterol or dioctadecyl-snglycero-phosphorylcholine / dipalmitoylphosphatidylglycerol/cholesterol liposomes. A somewhat less pronounced difference in rate of prodrug degradation was found when the liposomes were incubated with lysosomal fractions. The water-soluble products that were formed showed anti-tumor activity against C26-adenocarcinoma tumor cells in vitro. Preliminary evidence suggests this activity to be caused by 5-fluoro-2′-deoxyuridine.

We conclude that incubation of liposomes of varied composition containing diacylated 5-fluoro-2′deoxyuridine derivatives with Kupffer cells in culture, results in the formation of an intracellular prodrug depot in these cells from which compounds with anti-tumor activity are released with controllable rates.