We 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 3H-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.