Enantioselective release of 5-fluorouracil from N-(2-hydroxypropyl)methacrylamide-based copolymers via lysosomal enzymes.

Water soluble copolymers based on N-(2-hydroxypropyl)methacrylamide (HPMA) containing oligopeptide side chains terminated in an alpha-substituted glycine derivative of the anticancer compound 5-fluorouracil (5-FU) were synthesized by a new facilitated synthetic route and studied for their ability to release free 5-FU in the presence of lysosomal enzyme preparations. In addition, the properties of the low molecular weight alpha-substituted glycine derivatives were studied in the presence of lysosomal enzyme preparations and leucine aminopeptidase. The results revealed that (1) the stereochemistry (L vs D) of the alpha-substituted glycine derivative, (2) the hydrophobicity (Ala vs Leu) of the penultimate amino acid residue relative to the alpha-substituted glycine derivative, and (3) the total length of the oligopeptide sequence spacer (tetrapeptide vs hexapeptide) terminated in the alpha-substituted glycine derivative and the polymer carrier all directly influence the enzymatically catalyzed release of free 5-FU.