Published in Cancer Detection and Prevention 2000; 24(Supplement 1).

Selective transfer of a lipophilic prodrug of 5-fluorodeoxyuridine (FUdR) from immunoliposomes to colon cancer cells

GA Koning PhD 1,2, J Kamps PhD 1, GL Scherphof PhD 1

1 Dept Physiological Chemistry, Groningen University Institute for Drug Exploration, GUIDE Groningen;, 2 Dept Pharmaceutics, Utrecht University, Utrecht, The Netherlands,

AIM Immunoliposomes, liposomes with monoclonal antibodies attached, are being developed for targeting of the anticancer drug FUdR to colon cancer cells. METHODS A monoclonal antibody against the rat colon carcinoma CC531 was covalently coupled to liposomes containing a dipalmitoylated derivative of the anticancer drug FUdR (FUdR-dP) as a prodrug in their bilayers. We studied the in vitro anti-tumor activity of these liposomes and determined the mechanism by which the active drug FUdR is delivered intracellularly. Therefore, the fate of the liposomal bilayer markers cholesterol-[14C]-oleate and [3H-]cholesteryloleylether as well as the [3H]-labeled prodrug and colloidal gold as an encapsulated liposome marker were followed. RESULTS Immunoliposomes containing FUdR-dP caused a thirteen-fold stronger inhibition of CC531 cell growth in vitro than FUdR-dP in liposomes without antibody. After binding of the immunoliposomes to the cell surface only limited amounts were internalized. By contrast, already within 24 h immunoliposome-incorporated FUdR-dP was hydrolyzed virtually completely to the parent drug FUdR, intracellularly. This process was inhibited by a variety of endocytosis inhibitors, indicating that the prodrug enters and is processed by the cells by a mechanism involving an endocytic process. Based on these observations we tentatively conclude that during the interaction of the immunoliposomes with the tumor cells the lipophilic prodrug FUdR-dP is selectively transferred to the cell surface and internalized by constitutive endocytic processes. The prodrug is then transported to a lysosomal compartment where hydrolysis and release of parent drug takes place. CONCLUSIONS We developed a targeted liposomal formulation, which is able to deliver FUdR to colon carcinoma cells intracellularly with high efficiency, without the need for the cells to internalize the liposomes as such. This approach may be attractive for other lipophilic (anti-cancer) (pro)drugs. In this sense our system also serves as a model for the development of new lipid-based drug delivery systems for anti-cancer therapy.

KEY WORDS: Immunoliposomes, Selective transfer, Drug targeting, FUdR, Colon cancer.

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Paper presented at the International Symposium on Impact of Biotechnology on Cancer Diagnostic & Prognostic Indicators; Geneva, Switzerland; October 28 - 31, 2000; in the section on novel therapies.