PREPARATION AND PROPERTIES OF MONOMETHOXY POLY(ETHYLENE GLYCOL) DOXORUBICIN CONJUGATES LINKED BY AN AMINO-ACID OR A PEPTIDE AS SPACER

Polymeric doxorubicin prodrugs were prepared linking monomethoxy poly( ethylene glycol), 5000 D molecular weight, to the doxorubicin amino gr oup, using an amino acid or a peptide as a spacer arm. As spacers glyc ine, L-phenylalanine, L-tryptophan and glycil-L-valil-L-phenylalanine were used. The conjugates showed enhanced stability to alkaline degrad ation compared to the free doxorubicin. Towards Ehrlich solid tumor in mice the glycin spaced derivative was devoid of activity, whereas the phenylalanine and tryptophan derivatives were 20% and 16% active and the tripeptide one 50% active with respect to free doxorubicin. On the other hand the derivatization was accompanied by a great decrease of toxicity in mice with respect to the free drug. Doxorubicin was not re leased from conjugates by chymotrypsin incubation or in plasma.