Polymeric prodrug for release of an antitumoral agent by specific enzymes

The clinical usefulness of antitumor chemotherapy has been strongly limited by the lack of specificity of most anticancer drugs, which act also agains t healthy cells. The aim of this work was to design, synthesize, and evalua te a macromolecular prodrug of Cytarabine, a known antitumor drug, which is a specific substrate for plasmin enzyme whose concentration is high in var ious kinds of tumor mass as a result of plasminogen activator secretion. al pha,beta -Poly(N-hydroxyethyl)-DL-aspartamide (PHEA), a known synthetic and biocompatible polyamino acid, was used as a drug carrier, and Cytarabine w as linked to PHEA by D-Val-Leu-Lys spacer synthesized beginning from C-oz-D -Val-LeuOH dipeptide and N-6-CbzLys methyl ester. The content of Cytarabine in the purified PHEA-D-Val-Leu-Lys-Cytarabine conjugate was equal to 3% w/ w. In vitro experiments in the presence of plasmin evidenced the ability of this enzyme to strongly increase drug release from the macromolecular prod rug, as well as plasma incubation shows high stability of drug-polymer link age. The direct linkage of Cytarabine to PHEA was also performed and, like PHEA-D-Val-Leu-Lys-Cytarabine conjugate, the obtained PHEA-Cytarabine conju gate showed high stability in plasma, but no release of Cytarabine was reve aled in the presence of plasmin.