Release of Active Drug from Intracellular Liposomal Prodrug Depots in Macrophages Controlled by Liposome Composition

Abstract

Several drugs have limited potency due to their rapid elimination or inactivation. The anticancer drug 5-fluoro-deoxyuridine (FUdR), which is frequently used in therapeutic treatment of liver metastases from colon tumors, is an example of such drugs. It is rapidly eliminated from circulation and metabolized, mainly by the hepatocytes in the liver. Over the past few years we have investigated the possibility to keep the drug away from the hepatocytes and to save it from rapid inactivation by encapsulating it in liposomes. In this way the liposomal drug is expected to accumulate in the macrophages of the liver (Kupffer cells), which form a major target site for intravenously administered liposomes. There, as the liposomal structure is gradually degraded by lysosomal enzymes, the drug will be released, initially within the lysosomal compartment, while subsequently it will leak out of the lysosomes and eventually out of the cells so as to become available for uptake by intrahepatically situated tumor cells. In this contribution we describe this system for the prodrug dipalmitoyl-FUdR, incorporated in the liposomal bilayer, requiring an additional step for the drug to become available, i.e. the enzymatic deacylation of the prodrug. It is demonstrated that the rate of intralysosomal degradation of liposomes in Kupffer cells varies substantially with liposomal lipid composition and that the rate of release of active drug from the Kupffer cells parallels the rate of liposome degradation. In addition, it is demonstrated that in this way the antitumor activity of the FUdR can be enhanced by more than two orders of magnitude and that the degree of antitumor activity reflects, to a limited extent, the rate at which the liposomes are degraded.