Development of dual-acting prodrugs for circumventing multidrug resistance.
We have developed a novel dual-acting maleimide-bearing prodrug that incorporates the anticancer agent doxorubicin and an inhibitor of the P-glycoprotein efflux pump that is over-expressed in multidrug resistant tumor cells. Additionally, the prodrug contains a 1,6-self-immolative spacer coupled to the dipeptide Phe-Lys that acts as a substrate for cathepsin B. The prodrug, once bound through its maleimide moiety to the cysteine-34 group of human serum albumin, was cleaved by cathepsin B and in tumor homogenates demonstrating a release of the anticancer agent doxorubicin and the inhibitor.
Abu Ajaj
Khalid
K
Tumor Biology Center, Macromolecular Prodrugs, Breisacher Strasse 117, D-79106 Freiburg, Germany.
Kratz
Felix
F
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000737:chemistry; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology; D002401:Cathepsin B / Q000737:chemistry*; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D003545:Cysteine / Q000737:chemistry; D004317:Doxorubicin / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D018432:Drug Resistance, Multiple; D006801:Humans; D008239:Lysine / Q000737:chemistry; D010455:Peptides / Q000737:chemistry; D010649:Phenylalanine / Q000737:chemistry; D011355:Prodrugs / Q000138:chemical synthesis* / Q000494:pharmacology; D012709:Serum Albumin / Q000737:chemistry
D018435:ATP Binding Cassette Transporter, Subfamily B; D000970:Antineoplastic Agents; D010455:Peptides; D011355:Prodrugs; D012709:Serum Albumin; D010649:Phenylalanine; D004317:Doxorubicin; D002401:Cathepsin B; D008239:Lysine; D003545:Cysteine