Liposomes and immunoliposomes containing
cytotoxic agents may be highly efficacious in intracavity
therapy of
malignancies confined principally to the peritoneal cavity. To assess the feasibility of this locoregional treatment, we prepared two derivatives of
5-fluorouridine (5-FUR), 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 determined, and size analysis and differential scanning calorimetry were carried out to evaluate the
drug delivery potential of
liposomes containing
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 differential scanning calorimetry indicated as being firmly anchored to the
lipid bilayer. Thus,
5'-palmitoyl-5-FUR was chosen to prepare a chemotherapeutic
liposome-
monoclonal antibody conjugate (immunoliposome). The covalent linkage between antibody and
liposome was realized by coupling the thiolated
monoclonal antibody AR-3 with REV
liposomes, containing N-[4-(p-maleimidophenyl)butyryl]
phosphatidylethanolamine. The cytotoxic activity of
drug-bearing
liposomes and immunoliposomes was evaluated on the 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
liposomes or immunoliposomes into athymic mice ip grafted with human HT-29 cell line. In this mouse model, the immunoliposome containing
5'-palmitoyl-5-FUR displayed the best antitumoral activity, since on day 27 postgraft only 5% of
residual tumor mass was present, compared to control mice; there was a close relationship between exposure time of
tumor tissue to the
drug and antitumor potency.