ANTITUMORAL ACTIVITY OF LIPOSOMES AND IMMUNOLIPOSOMES CONTAINING 5-FLUOROURIDINE PRODRUGS

Liposomes and immunoliposomes containing cytotoxic agents may be highl y efficacious in intracavity therapy of malignancies confined principa lly to the peritoneal cavity. To assess the feasibility of this locore gional treatment, we prepared two derivatives of 5-fluorouridine (5-FU R), a highly cytotoxic metabolite of 5-fluorouracile, and incorporated them into REV liposomes, prepared with the reverse phase evaporation method. Encapsulation efficiency, drug leakage, and stability were det ermined, and size analysis and differential scanning calorimetry were carried out to evaluate the drug delivery potential of liposomes conta ining 5'-palmitoyl-5-FUR, 5'-succinyl-5-FUR, or the parent drug 5-FUR, The most suitable drug for encapsulation, in terms of minimum leakage and encapsulation efficiency, was 5'-palmitoyl-5-FUR, which different ial scanning calorimetry indicated as being firmly anchored to the lip id bilayer. Thus, 5'-palmitoyl-5-FUR was chosen to prepare a chemother apeutic liposome-monoclonal antibody conjugate (immunoliposome). The c ovalent linkage between antibody and liposome was realized by coupling the thiolated monoclonal antibody AR-3 with REV liposomes, containing -maleimidophenyl)butyryl]phosphatidylethanolamine. The cytotoxic acti vity of drug-bearing liposomes and immunoliposomes was evaluated on th e HT-29 human colon adenocarcinoma cell line; the immunoliposomes had higher cytotoxicity than liposomes or 5-FUR. To explore the potential of these drug formulations in anticancer therapy, we ip injected lipos omes or immunoliposomes into athymic mice ip grafted with human HT-29 cell line, in this mouse model, the immunoliposome containing 5'-palmi toyl-5-FUR displayed the best antitumoral activity, since on day 27 po stgraft only 5% of residual tumor mass was present, compared to contro l mice: there was a close relationship between exposure time of tumor tissue to the drug and antitumor potency.