Characterization of a lipophilic prodrug of 5-fluorouracil with a cholesterol promoiety and its application to liposomes.

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Abstract
A lipophilic prodrug of 5-fluorouracil (FU) with a cholesterol promoiety, cholesteryl-5-(5-fluorouracilcarbamoyl)capronate (ChFU), was synthesized and its physicochemical and biological properties were studied in comparison with those of octadecylcarbamoyl FU (C18FU) having the same linkage structure. ChFU and C18FU showed enhanced lipophilicity and almost complete incorporation into liposomes while incorporation of FU was very small. In neutral and alkaline media, FU was rapidly regenerated from ChFU with a half-life of about 14 min and C18FU showed a similar rapid conversion. The conversion of ChFU to FU was suppressed by the incorporation into liposomes and the regenerated FU was released from liposomes with a half-life of about 1 h. The release of FU from the liposomal formulation of C18FU was much slower than that of ChFU. The liposomal formation of ChFU showed almost the same in vivo antitumor activity against P388 leukemia as that of FU solution with less side effects. The liposomal formulation of C18FU exhibited superior in vivo antitumor effect to those of ChFU and free FU. The mode of incoporation of these lipophilic FU prodrugs into liposomes seemed to affect the conversion kinetics of the prodrugs and their subsequent pharmacological efficacy.

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