Preparation and properties of monomethoxy poly(ethylene glycol)-doxorubicin conjugates linked by an amino acid or peptide as spacer

Polymeric doxorubicin prodrugs were prepared linking monomethoxy
poly(ethylene glycol), 5000 D molecular weight, to the doxorubicin amino group,
using an amino acid or a peptide as a spacer arm. As spacers glycine, Lphenylalanine,
L-tryptophan and glycil-L-valil-L-phenylalanine were used. The
conjugates showed enhanced stability to alkaline degradation 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 released from
conjugates by chymotrypsin incubation or in plasma