Antiproliferative effect of immunoliposomes containing 5-fluorodeoxyuridine-dipalmitate on colon cancer cells

Abstract

SummaryWe have investigated the antiproliferative action towards CC531 colon adenocarcinoma cells of target cell-specific immunoliposomes containing the amphiphilic dipalmitoyl derivative of 5-fluorodeoxyuridine (FUdR-dP). FUdR-dP incorporated in immunoliposomes caused a 13-fold stronger inhibition of CC531 cell growth in vitro, during a 72-h treatment, than FUdR-dP in liposomes without antibody, demonstrating that the prodrug is efficiently hydrolysed to yield the active drug, FUdR, intracellularly. The intracellular release of active FUdR was confirmed by determining the fate of 3 H-labelled immunoliposomal FUdR-dP. Treatments shorter than 72 h with FUdR-dP in immunoliposomes resulted in anti-tumour activities comparable to, or even higher than, that of free FUdR. The shorter treatments reflect more closely the in vivo situation and illustrate the potential advantage of the use of immunoliposomes over non-targeted liposomal FUdR-dP or free FUdR. Association of tumour cell-specific immunoliposomes with CC531 cells was up to tenfold higher than that of liposomes without antibody or with irrelevant IgG coupled, demonstrating a specific interaction between liposomes and target cells which causes an efficient intracellular delivery of the drug. Since biochemical evidence indicates a lack of internalization or degradation of the liposomes as such, we postulate that entry of the drug most likely involves the direct transfer of the prodrug from the immunoliposome to the cell membrane during its antigen-specific interaction with the cells, followed by hydrolysis of FUdR-dP leading to relatively high intracellular FUdR-levels. In conclusion, we describe a targeted liposomal formulation for the anticancer drug FUdR, which is able to deliver the active drug to colon carcinoma cells with high efficiency, without the need for the cells to internalize the liposomes as such.

Coformulated N-Octanoyl-glucosylceramide Improves Cellular Delivery and Cytotoxicity of Liposomal Doxorubicin

“…A similar transfer to tumor cell membranes was described for the liposomal bilayer-incorporated prodrug 5-fluorodeoxyuridine-dipalmitate (Koning et al, 1999).…”

“…We know that PEG-liposomes, due to their hydrophilic coating, are not taken up by cells and do not fuse with the plasma membrane (Koning et al, 1999Everts et al, 2003). Instead, their doxorubicin content is gradually released free into the surrounding medium, from where it is then taken up by neighboring cells (Horowitz et al, 1992;Harasym et al, 1997).…”

EGFR targeted thermosensitive liposomes: A novel multifunctional platform for simultaneous tumor targeted and stimulus responsive drug delivery

“…Stealth properties which can be achieved by PEGylation process are also essential for long circulation residence and accumulation at the target site [3]. Despite the importance of PEGylation in achieving long nanocarrier circulation times, it can result in an effective barrier to nanoparticles uptake in tumor cells mainly due to hydrophilic steric hindrance [4,5].…”

A New Class of 5-Fluoro-2?-deoxyuridine Prodrugs Conjugated with a Tumor-Homing Cyclic Peptide CNGRC by Ester Linkers: Synthesis, Reactivity, and Tumor-Cell?Selective Cytotoxicity

“…There is also a different family of prodrugs that are activated to release 5-FdUrd by ionizing radiation (7,8) or UV light (9). For more sophisticated current 5-FdUrd prodrugs, targeting strategies are used to improve the efficiency of drug delivery into tumor tissues: for example, packaging of 5-FdUrd or its prodrugs into the nanoparticles (10,11), and conjugation of 5-FdUrd with tumor-cell-targeting antibodies (12). These drug delivery systems consist of nanoparticles that can readily be transported to the well vascularized region, but not to the ischemic region with less vascularization, of tumor tissues (13)(14)(15).…”