INCORPORATION OF LIPOPHILIC PRODRUGS OF AMETANTRONE AND MITOXANTRONE INSIDE LOW-DENSITY LIPOPROTEINS(LDL) AND SELECTIVE UPTAKE OF THE PRODRUG LDL COMPLEX VIA THE LDL RECEPTOR PATHWAY

Low-density lipoprotein (LDL) particles are potential drug carriers, b ut only lipophilic drug species partition into the core of the system. In this study, ametantrone (AQ) and mitoxantrone (DHAQ) have been cou pled to different fatty acids (stearate, palmitate, oleate, linolenate ). The linolenate esters of AQ and DHAQ incorporate in highest concent ration into LDL using the following protocol of incubation. The prodru g (dilinolenate of DHAQ) was dissolved in Intralipid (a parenteral tri glyceride rich emulsion) and then incubated with LDL and lipoprotein d eficient serum or albumin for 18 hours at 37-degrees-C. This method pr ovides substantial incorporation of dilinolenate-DHAQ into LDL (26 +/- 5 molecules of dilinolenate-DHAQ per LDL particle). The dilinolenate- DHAQ-LDL complex was recognized by apolipoprotein B and E receptors, i n vitro and in vivo in the rabbit. The pharmacological efficiency of b oth free dilinolenate-DHAQ and dilinolenate-DHAQ-LDL complex was 1000 times less cytotoxic on A 549, A 431 and L 1210 cells than free DHAQ. We conclude that this method of incorporation allows the incorporation of a consistent concentration of prodrug inside LDL and prevents aggr egation of the lipoprotein during the preparation of the prodrug-LDL c omplex. This complex is incorporated into the cell both in vitro and i n vivo via the LDL receptor pathway.