Premium
Polymeric prodrugs of mitomycin C
Author(s) -
Soyez Heidi,
Schacht Etienne,
De Marre Anne,
Seymour Leonard W.
Publication year - 1996
Publication title -
macromolecular symposia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.257
H-Index - 76
eISSN - 1521-3900
pISSN - 1022-1360
DOI - 10.1002/masy.19961030117
Subject(s) - prodrug , conjugate , mitomycin c , chemistry , tripeptide , collagenase , oligopeptide , protease , biochemistry , enzyme , stereochemistry , peptide , biology , mathematical analysis , mathematics , genetics
Poly‐[N‐(2‐hydroxyethyl)‐L‐glutamine] (PHEG) prodrugs of the cytotoxic agent Mitomycin C were synthesized using peptidyl spacers to link the drug to the polymeric carrier. The influence on the length and detailed structure of the oligopeptide on the rate of drug release was investigated in buffer, in the presence of lysosomal enzymes (tritosomes, cathepsin B and D) and metalloprotease type IV collagenase. It was observed that tetra‐ and hexapeptide based conjugates generally release Mitomycin C (MMC) more effectively than tripeptide derivatives. The gly‐phe‐ala‐leu conjugate released MMC very rapidly both in presence of lysosomal enzymes and collagenase IV. Only in the presence of the aspartic protease cathepsin D, the gly‐phe‐leu‐gly‐phe‐leu derivative turned out to be a better substrate. In vivo studies against C26 solid tumour bearing mice suggest that PHEG‐spacer‐MMC conjugates act as prodrugs of MMC: antitumour efficacy of the macromolecular prodrugs was better than free MMC both in inhibition of tumour growth and increasing survival.