Stable incorporation of a lipophilic daunorubicin prodrug into apolipoprotein E-exposing liposomes induces uptake of prodrug via low-density lipoprotein receptor in vivo

Many tumors express elevated levels of low-density lipoprotein (LDL) recept ors. Therefore, native LDL and synthetic LDL-like particles have been propo sed as carriers for antineoplastic drugs. We demonstrated earlier that smal l apolipoprotein E (apoE)-exposing liposomes were specifically recognized b y the LDL receptor. In this study, we incorporated a lipophilic derivative of daunorubicin (LAD) into the apoE liposomes. Up to 11 molecules of LAD co uld be incorporated per particle without significantly changing the size, l ipid composition, and ability to bind apoE of the liposomes. The biological fate of the prodrug was largely determined by its carrier (70% of the init ially incorporated LAD was still associated to the liposomes after 4 h of c irculation in mice). Compared with free daunorubicin, the circulation half- life of the liposome-associated prodrug was substantially prolonged and und esired tissue disposition was reduced. The role of the LDL receptor in the metabolism of LAD-loaded apoE liposomes was demonstrated in rats with up-re gulated hepatic LDL receptors. In these rats, the liver uptake of the prodr ug and carrier was increased 5-fold. The addition of apoE was essential for LDL receptor-mediated uptake of the drug-carrier complex. In LDL receptor- deficient mice, the circulation time of both the prodrug and the carrier in creased approximately 2-fold compared with wild-type mice. We conclude that LAD-loaded apoE liposomes constitute a stable drug-carrier complex that is well suited for LDL receptor-mediated selective drug delivery to tumors.