Anti-tumor activity of daunorubicin linked to poly-L-aspartic acid

Daunorubicin was bound to poly-L-aspartic acid via the methylketone side chain of the drug to avoid reaction of the sugar amino group believed to be essential for optimal drug activity. Attachment of the drug to the polyamino acid by an ester linkage was achieved by nucleophylic substitution reaction of 14-bromo-daunorubicin. Compared with free daunorubicin, the polymeric derivative was less cytotoxic to HeLa cells in vitro, but more effective against all tumor models tested (P388 leukemia, Gross leukemia, MS-2 sarcoma). The binding to the polypeptide markedly reduced drug toxicity but only slightly decreased drug potency. The daunorubicin-poly-L-aspartic acid conjugate demonstrated antitumor activity comparable to that of doxorubicin in leukemia models, but superior to that of doxorubicin in a solid tumor model (MS-2 sarcoma).