Targeting of an antitumor agent, RS-1541 (palmitoyl-rhizoxin), via low-density lipoprotein receptor

Abstract

RS-1541 is a 13- O-palmitoyl derivative of rhizoxin, an inhibitor of tubulin polymerization. RS-1541 has been shown to bind preferentially to plasma lipoproteins and to exhibit selective uptake by tumors in mice. We demonstrated that: (1) 99% of RS-1541 bound to human lipoproteins after incubation with human serum, among which the low-density lipoprotein (LDL) fraction attained 10%; (2) RS-1541/LDL complex was obtained by simply incubating human native LDL with a detergent-aided RS-1541 solution; (3) uptake of the [ 14C]RS-1541/LDL complex in cultured human skin fibroblasts was dependent on the LDL receptor activities of the cells; (4) excess amounts of native LDL or 10 μM monensin, a proton ionophore, significantly inhibited the uptake; and (5) the detergent-aided solution of [ 14C]RS-1541 showed very low cellular uptake. These results suggest the possibility of LDL as an endogenous targeting carrier of RS-1541 into tumor cells, which have higher LDL receptor activities.