Previous studies have demonstrated that human leukemic cells and certain cancer cells in culture have a higher uptake of plasma low-density lipoprotein (LDL) than the corresponding normal cells. Therefore LDL has been proposed as a drug carrier for anticancer agents. In the present investigation, we have developed a method to incorporate a lipophilic derivative of doxorubicin, N-trifluoroacetyladriamycin-14-valerate, into LDL. The method involves lyophilization of LDL in the presence of sucrose as protective agent and gives an N-trifluoroacetyladriamycin-14-valerate-LDL complex containing about 100 drug molecules per LDL particle. The in vivo fate of the complex in mice as judged from the disappearance from plasma and accumulation in organs was similar to that of native LDL. When cultured human fibroblasts were incubated with N-trifluoroacetyladriamycin-14-valerate-LDL, cellular drug accumulation was dependent on the LDL receptor activity of the cells. The covalent linkage of two anthracycline derivatives to lysine residues of LDL yielded conjugates with drug/LDL molar ratios ranging up to 80. With increasing substitution, there was a progressive decline in the affinity of the conjugate for the LDL receptor in vitro. The in vivo fate of such conjugates was quite similar to that of native LDL. We conclude that it is possible to associate cytotoxic agents with LDL without interfering with its in vivo behavior.

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Supported by grants from the Swedish Medical Research Council, the Cancer Society in Stockholm, and the Baltzar W. A. von Platen Foundation.

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