title: Macromolecular attachment as a metabolic stabilizer for a labile radiosensitizer.
abstract: 4-Nitro-5-sulfonylimidazoles represent a class of hypoxic cell radiation sensitizers whose in vitro activity greatly exceeds that of the current clinical standard, misonidazole. However, in vivo studies with these 4,5-disubstituted imidazoles have shown that a rapid reaction with circulating thiols decomposes the agent and compromises its clinical utility. Drug-macromolecule conjugates prepared in this study from poly-L-glutamate, succinylated poly-L-lysine, dextran, and a succinylated polylysine-antibody, all demonstrated protection of the drug from glutathione displacement. 1-Methyl-4-nitro-5-imidazolyl 4-aminophenyl sulfone conjugated to a succinylated poly-L-lysine-antibody was greater than 7 times less reactive than the unbound drug. Polymer transport may offer a useful tumor-delivery mechanism for these highly reactive radiation sensitizers.
mesh_terms: D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm / Q000276:immunology; D000954:Antigens, Surface / Q000276:immunology; D055598:Chemical Phenomena; D002621:Chemistry; D003911:Dextrans; D005978:Glutathione; D046911:Macromolecular Substances; D009593:Nitroimidazoles; D011099:Polyglutamic Acid; D011107:Polylysine / Q000031:analogs & derivatives; D011838:Radiation-Sensitizing Agents; D013386:Succinates; D013450:Sulfones
chemical_list: D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D000954:Antigens, Surface; D003911:Dextrans; D046911:Macromolecular Substances; D009593:Nitroimidazoles; D011838:Radiation-Sensitizing Agents; D013386:Succinates; D013450:Sulfones; D011107:Polylysine; D011099:Polyglutamic Acid; D005978:Glutathione