INVITRO STABILITY AND CYTOSTATIC ACTIVITY OF LIPOSOMAL FORMULATIONS OF 5-FLUORO-2'-DEOXYURIDINE AND ITS DIACYLATED DERIVATIVES

The water-soluble antineoplastic agent 5-fluoro-2'-deoxyuridine (FUdR) was encapsulated in the water phase of liposomes of different lipid c ompositions. The retention of this drug upon storage and during contac t with plasma was assessed. It was found that, upon refrigeration, dif fusion of FUdR across the liposome bilayer was considerably faster whe n the drug was encapsulated in fluid-type liposomes (egg PC/PS/CHOL) t han in solid-type liposomes (DSPC/DPPG/CHOL). With either composition, leakage of the drug from the liposomes was accelerated upon contact w ith plasma. To achieve improved liposomal retention of the drug, FUdR was converted to a lipophilic prodrug by esterifying the free hydroxyl groups in the deoxyribose moiety with fatty acids of different chain lengths. Thus FUdR-dipalmitate (C-16) and FUdR-dioctanoate (C-8) were synthesized and incorporated in liposomes. The dipalmitoyl derivative could be incorporated upto 13 mol% in solid-type liposomes but to only 2 mol% in fluid-type liposomes. Freeze-fracture electron microscopy r evealed no major differences between control liposomes and those conta ining the prodrug. FUdR-dipalmitate was found to be firmly associated with the liposomal bilayer in both liposome-types: no exchange of the pro-drug with blood constituents or hydrolysis by serum esterases coul d be registered when the liposomes were incubated with serum. On the o ther hand, liposome-incorporated FUdR-dioctanoate was found to be read ily extracted from the liposomes by serum components (predominantly al bumin) and was found to be degraded rapidly by serum esterase activity . The antitumor activity of FUdR-prodrugs was determined using C26 col on adenocarcinoma cells. This cell line was found to be highly sensiti ve to FUdR. Liposomal FUdR-dioctanoate inhibited cell growth in the sa me concentration range as unesterified FUdR. FUdR-dipalmitate, however , was more than two orders of magnitude less potent in inhibiting cell proliferation. Its antiproliferative activity was dependent on the li posome-type used: when incorporated in fluid-type liposomes, antiproli ferative activity of FUdR-dipalmitate was several-fold higher than in solid-type liposomes. The difference in antitumor activity between FUd R-dipalmitate and FUdR-dioctanoate and between FUdR-dipalmitate in the fluid- and solid-type liposomes could be explained by differences in the rate of hydrolysis of the prodrugs to FUdR by esterase activity in the tumor cells or in the growth medium.