p-Benzylthiocarbamoyl-aspartyl-daunorubicin-substituted polytrisacryl. A new drug acid-labile arm-carrier conjugate.
A new type of drug acid-labile arm-carrier is described. A hydrophilic polymer [polytrisacryl, or poly(acryloyl 2-amido-2-hydroxymethyl-1,3-propanediol)], used as a model, is substituted with p-nitrobenzyl groups. The nitrobenzyl groups are reduced to aminobenzyl and transformed into benzylisothiocyanate groups which are allowed to react with aminoacyl daunorubicin. The excess of benzylisothiocyanate is transformed into benzylthiocarbamoyl N-methyl glucamine. A conjugate containing benzylthiocarbamoyl-aspartyl daunorubicin is stable at neutral pH, and releases free daunorubicin when it is exposed to pH 5 or below. This conjugate is about 200-fold less toxic than free daunorubicin, on a molecular basis, when it is added to the medium of Lewis lung carcinoma (3LL) cells in culture.
Daussin
F
F
Laboratoire de Biochimie Cellulaire et Moléculaire des Glycoconjugués, Centre de Biophysique Moléculaire, Centre National de la Recherche Scientifique, Orléans, France.
Boschetti
E
E
Delmotte
F
F
Monsigny
M
M
D000179:Acrylates / Q000633:toxicity*; D001224:Aspartic Acid / Q000633:toxicity; D001665:Binding Sites; D002277:Carcinoma / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D003630:Daunorubicin / Q000031:analogs & derivatives* / Q000633:toxicity; D006863:Hydrogen-Ion Concentration; D008175:Lung Neoplasms / Q000378:metabolism; D014677:Pharmaceutical Vehicles; D013859:Thiocarbamates / Q000633:toxicity; D014407:Tumor Cells, Cultured
D000179:Acrylates; D014677:Pharmaceutical Vehicles; D013859:Thiocarbamates; D001224:Aspartic Acid; C036658:acrylic acid; D003630:Daunorubicin