Low density lipoprotein receptor-mediated delivery of a lipophilic daunorubicin derivative to B16 tumours in mice using apolipoprotein E-enriched liposomes

Many tumours express relatively high levels of low-density lipoprotein (LDL ) receptors on their membranes. The LDL receptor is, therefore, an attracti ve target for the selective delivery of antineoplastic drugs to tumour cell s. We reported previously on the synthesis of small apolipoprotein E (apoE) -containing liposomes that behave in vivo in a very similar way to native L DL. In this study, we examined the interaction of this liposomal carrier wi th cultured B16 melanoma cells. Binding of apoE liposomes to the cells is s aturable, with a maximum binding of approximately 90 000 particles per cell . Cross-competition studies indicated that apoE liposomes are bound by the LDL receptor. Association of apoE liposomes to B16 cells is strictly Ca2+ d ependent, which forms additional evidence for a role of the LDL receptor. T he affinity of apoE liposomes for the LDL receptor on B16 cells is 15-fold higher than that of LDL (0.77 vs 11.5 nM respectively). ApoE is essential f or the LDL receptor recognition because liposomes lacking apoE were, in com petition studies, 20- to 50-fold less effective than apoE-containing liposo mes. We examined in B16 tumour-bearing mice the tumour-localizing propertie s of apoE liposomes and the disposition of an incorporated lipophilic deriv ative of daunorubicin (LAD). Tissue distribution studies showed that LAD-lo aded apoE liposomes were taken up and processed by the major LDL receptor-e xpressing organs (i.e. adrenals, liver and spleen). Of all other tissues, t he tumour showed the highest uptake. The distribution patterns of LAD-loade d apoE liposomes and native LDL in the tumour-bearing mice were very simila r, which supports the role of the LDL receptor in the disposition of the pr odrug-loaded particles. The disposition of LAD followed the pattern of the liposomal carrier. We conclude that apoE liposomes enable LDL receptor-medi ated specific delivery of antineoplastic (pro)drugs to tumours, and, theref ore, constitute an attractive novel option for anti-tumour chemotherapy.