Low density lipoprotein and liposome mediated uptake and cytotoxic effect of N-4-octadecyl-1-beta-D-arabinofuranosylcytosine in Daudi lymphoma cells

Low density lipoprotein (LDL) receptor-mediated uptake and cytotoxic effect s of N-4-octadecyl-1-beta-D-arabinofuranosylcytosine (NOAC) were studied in Daudi lymphoma cells. NOAC was either incorporated into LDL or liposomes t o compare specific and unspecific uptake mechanisms. Binding of LDL to Daud i cells was not altered after NOAC incorporation (K-D 60 nM). Binding of li posomal NOAC was not saturable with increasing concentrations. Specific bin ding of NOAC-LDL to Daudi cells was five times higher than to human lymphoc ytes. LDL receptor binding could be blocked and up- or down-regulated. Go-i ncubation with colchicine reduced NOAC-LDL uptake by 36%. These results sug gested that NOAC-LDL is taken up via the LDL receptor pathway. In an in vit ro cytotoxicity test, the IC50 of NOAC-LDL was about 160 mu M, whereas with liposomal NOAC the IC50 was 40 mu M. Blocking the LDL receptors with empty LDL protected 50% of the cells from NOAC cytotoxicity. The cellular distri bution of NOAC-LDL or NOAC-liposomes differed only in the membrane and nucl ei fraction with 13% and 6% respectively Although it is more convenient to prepare NOAC-liposomes as compared to the loading of LDL particles with the drug, the receptor-mediated uptake of NOAC-LDL provides an interesting rat ionale for the specific delivery of the drug to tumours that express elevat ed numbers of LDL receptors.