Macromolecular prodrugs of 5-fluorouracil .2. Enzymatic degradation

Polymeric conjugates of 5-fluorouracil were synthesized by the covalent attachment of oligopeptide chains, having a 2-(5-fluorouracil-1-yl)glycine ethyl ester residue at the C-terminus, to poly(ethylene glycol), dextran and poly[N-5-(2-hydroxyethyl)-L-glutamine]. In order to determine their ability to release the free drug by a specific enzymatic process catalyzed by proteinases occurring at the target site, the polymeric conjugates were incubated with three tumor-associated enzymes (collagenase, cathepsin B and cathepsin D) and a mixture of lysosomal enzymes. The enzymes hydrolysed to various extents one or two peptide bonds of the oligopeptide chains attached to polymer carriers. The position and rate of cleavage depended on the enzyme, the composition and configuration of the oligopeptide chain, and on the polymer carrier. PEG[Gly-Phe-Ala-Gly(FU)OEt](2) (1) conjugate was preferentially hydrolysed by collagenase, with the release of tripeptide Phe-Ala-Gly(FU)OR (1). PEG, dextran and PHEG conjugates having Gly-Phe-Gly-Gly(FU)OEt (l,d) as attached oligopeptide chain released free 5-FU in the presence of cathepsin B, with a rate determined by the polymeric carrier: PEG > PHEG > dextran. Finally, PEG conjugates with Gly-Phe-Gly-Gly(FU)OEt (I,d) and Gly-Phe-Phe-Gly(FU)OEt (d) chains released free 5-FU very rapidly in the presence of lysosomal enzymes.