Liposome-incorporated 3',5'-O-dipalmitoyl-5-fluoro-2'-deoxyuridine as a slow-release anti-tumor drug depot in rat liver macrophages.

Abstract

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/cholest ero l or dioctadecyl-sn-glycero-phosphorylcholine/dipalmitoylphosphatidylg lycerol/ 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.

• Authors: M Van Borssum Waalkes, G L Scherphof
• Journal: Selective cancer therapeutics (Sel Cancer Ther) Vol. 6 Issue 1 Pg. 15-22 ( 1990) ISSN: 1043-0733 [Print] United States
• PMID: 2140463 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Delayed-Action Preparations
• Liposomes
• Prodrugs
• Floxuridine
• 3',5'-O-dipalmitoyl-5-fluoro-2'-deoxyuridine

Topics

• Animals
• Antineoplastic Agents (administration & dosage, chemical synthesis, pharmacokinetics)
• Cell Division
• Delayed-Action Preparations
• Floxuridine (administration & dosage, analogs & derivatives, chemical synthesis, pharmacokinetics)
• Kupffer Cells (drug effects, metabolism)
• Liposomes
• Liver (drug effects, metabolism)
• Macrophages (drug effects, metabolism)
• Prodrugs (chemical synthesis, pharmacology)
• Tumor Cells, Cultured (drug effects)