Antitumoral Activity of Liposomes and Immunoliposomes Containing 5-Fluorouridine Prodrugs

Abstract

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.

Cisplatin encapsulated in phosphatidylethanolamine liposomes enhances the in vitro cytotoxicity and in vivo intratumor drug accumulation against melanomas

“…Fusion of the biological membrane or endocytosis may involve this inverted structure. Previous studies suggested the excellent ability to facilitate drug or gene delivery into cells by PE [27,28]. Another mechanism of PE uptake by cells may be the transbilayer internalization pathway [12].…”

Development and Characterization of Oligonucleotide-Tagged Dye-Encapsulating EPC/DPPG Liposomes

“…Quantification is finally achieved through measuring the absorbance of TNB −2 at 412 nm and by using a calibration curve. 38 …”

Comparison of Nanogel Drug Carriers and their Formulations with Nucleoside 5′-Triphosphates

“…As an example, encapsulation of a series of 4-(N)-acylated prodrugs of gemcitabine in liposomes can be mentioned (10). However, many small water-soluble molecules, such as ara-C, a NA related to gemcitabine, and 5-fluorouridine, diffused rapidly through the liposome bilayer, thus limiting the shelf life and clinical usefulness of these liposomal drug formulations (11,12). These findings strongly suggest the need to develop a new efficient drug delivery system for NA.…”