SYNTHESIS OF A LIPOPHILIC DAUNORUBICIN DERIVATIVE AND ITS INCORPORATION INTO LIPIDIC CARRIERS DEVELOPED FOR LDL RECEPTOR-MEDIATED TUMOR-THERAPY

Purpose. Many tumors express elevated levels of LDL receptors (apoB, E receptors) on their membranes. Selective delivery of anti-neoplastic drugs to tumors by incorporation of these drugs into LDL or LDL-resemb ling particles should improve the efficacy of tumor therapy and minimi ze the severe side-effects. Since the apolipoproteins oil the particle s are essential for the LDL receptor recognition, drugs should prefera bly be incorporated into the lipid moiety. Most anti-tumor agents are too hydrophilic for incorporation into these carriers. Methods. We syn thesized LAD, a lipophilic prodrug of daunorubicin, by coupling the dr ug via a lysosomally degradable peptide spacer to a cholesteryl oleate analog. Results. The overall yield of the synthesis was 50% with a pu rity of >90%. Radioactively ([H-3]) labeled LAD was obtained via a sli ghtly modified procedure (yield 40%). The octanol/water partition coef fient of LAD is 30-fold higher than that of daunorubicin. LAD could be incorporated into triglyceride-rich lipid emulsions and small liposom es, which, if provided with apoE, have been demonstrated earlier to be cleared in vivo via the LDL receptor. The liposomes contained approxi mately 10 molecules of LAD per liposomal particle. Analysis of differe ntly sized LAD-containing emulsions suggests that LAD associates with the surface of lipidic particles. In the presence of human serum, LAD did not dissociate from the emulsion particles, indicating a firm asso ciation of LAD with the carrier. Conclusions. The coupling of a choles terol ester analog to daunorubicin results in a lipophilic prodrug tha t can be firmly anchored into lipidic carriers. LAD-loaded emulsions a nd liposomes provided with recombinant apoE will be tested in the near future for their ability to deliver LAD to tumor tissue in vivo via t he LDL receptor.