The antitumour effect of lipophilic derivatives of 5-fluoro-2'-deoxyuridine incorporated into liposomes

Abstract

Lipophilic prodrugs of 5-fluoro-2'-deoxyuridine (FUdR), namely 5'-O-palmitoyl-5-fluoro-2'-deoxyuridine (5'-O-palm-FUdR) and 3',5'-O-dipalmitoyl 5-fluoro-2'-deoxyuridine (3',5'-O-dipalm-FUdR), were incorporated into bilayer liposomes. Prodrug incorporation into positively charged liposomes was quan titative and stable, homogeneous bilayer vesicles were obtained. The maximal amounts of prodrug incorporation are 200 μg for 5'-O-palm-FUdR and 90 μg for 3',5'-O-dipalm-FUdR per mg egg phosphatidylcholine as matrix lipid.

The prodrug-liposome preparations were tested in vivo against mammary carcinoma 13/C, Lewis lung carcinoma and L1210 leukaemia and compared to the cytostatic activity of free FUdR and of the prodrugs dissolved in peanut oil. Intraperitoneally administered prodrugs either incorporated into liposomes or dissolved in peanut oil inhibited tumour growth in all animals. The comparison of the doses required for tumour growth inhibition showed that both prodrugs were active at concentrations 20–75 times lower as compared to unmodified FUdR. However, due to the increased toxicity of the prodrug-liposome preparations, the therapeutic index of the parent drug FUdR could not be improved. The cytostatic effect of the prodrug preparations may be explained by altered pharmacokinetic properties of the FUdR derivatives and the additional sustained release action the liposomes are providing. A further increase of the antitumour activity may be obtained by the attachment of tumour-specific antibodies to the surface of such prodrug-containing liposomes.