Prolonged serum half-life of antineoplastic drugs by incorporation into the low density lipoprotein.

In vitro and in vivo data have indicated that tumor cells actively internalize the low density lipoprotein (LDL) from the circulation. In order to achieve a selective delivery of drugs to tumor cells via the LDL pathway, we have incorporated oleyl derivatives of methotrexate and floxuridine (FdUrd) into LDL particles. Three different incorporation procedures were studied: Method A, the dry film method; Method B, the transfer protein method; and Method C, the delipidation-reconstitution method. In all cases, 3H-labeled drug was incorporated into 125I-labeled LDL to yield double-labeled particles so that the behavior of both drug and carrier could be followed simultaneously. The last method led to the highest drug loading and it was possible to incorporate 50-70 molecules of dioleoyl-FdUrd per LDL particle as compared with about 18 molecules of drug when utilizing the transfer protein procedure. In vitro studies on the interaction of dioleoyl-FdUrd-LDL particles, obtained by the delipidation-reconstitution method, with the hepatocellular carcinoma cell line Hep G2, indicated that these reconstituted particles were equally effective in competing for LDL binding as native LDL. Moreover, drug delivery to Hep G2 cells occurred at the same rate as cellular association of the apolipoprotein B. In vivo studies on the fate of dioleoyl-FdUrd-LDL complexes in rats indicated that the serum decay was increased as compared with native LDL. The half-life of 6-9 min is, however, considerably prolonged as compared to the free drug (t1/2 less than 1 min). It is suggested that the 6-fold increased serum half-life of the drug-LDL complex accompanied by the possibly more specific tumor delivery may lead to an increased therapeutic effect.