In vivodistribution and antitumour activity of liposomal 3′,5′-O-dipalmitoyl-5-fluoro-2′-deoxyuridine

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Abstract
3′,5′-O-dipalmitoyl-5-fluoro-2′-deoxyuridine (FUdR-dipalmitate), a lipophilic prodrug of 5-fluoro-2′-deoxyuridine (FUdR), was incorporated in different types of liposomes. The in vivo distribution and intrahepatic deacylation of liposomal FUdR-dipalmitate was found to be strongly dependent on liposome composition and on drug to lipid ratio. The use of fluid-type liposomes (egg PC/PS/CHOL) rendered FUdR-dipalmitate more susceptible to enzymatic breakdown than solid-type liposomes (DSPC/DPPG/CHOL). A decrease of the retention of the drug in the body was also obtained when FUdR-dipalmitate was incorporated in solid-type liposomes with high drug to lipid ratio (1:10) than with low ratio (1:50). In spite of these substantial differences in the rates at which FUdR was liberated from liposomes with different fluidity, size, or drug to lipid ratio, only minor differences in therapeutic effect were observed in a number of murine tumour models (P388 leukaemia, Lewis Lung carcinoma, B16 melanoma and a C26 adenocarcinoma liver metastasis model). The lipophilic prodrug of FUdR exhibited antitumour activity at 100–600 times lower doses than the free drug. However, at these therapeutic doses FUdR-dipalmitate was also far more toxic. This prohibited the use of higher doses to increase antitumour activity.