title: Albumin-binding prodrugs of camptothecin and doxorubicin with an Ala-Leu-Ala-Leu-linker that are cleaved by cathepsin B: synthesis and antitumor efficacy.
abstract: We have recently validated a macromolecular prodrug strategy for improved cancer chemotherapy based on two features: (a) rapid and selective binding of thiol-reactive prodrugs to the cysteine-34 position of endogenous albumin and (b) acid-sensitive promoted or enzymatic release of the drug at the tumor site [Kratz, F., Warnecke, A., Scheuemann, K., Stockmar, C., Schwab, J., Lazar, P., Druckes, P., Esser, N., Drevs, J., Rognan, D., Bissantz, C., Hinderling, C., Folkers, G., Fichtner, I., and Unger, C. (2002) J. Med. Chem. 45, 5523-33]. In the present work, we developed water-soluble camptothecin (CPT) and doxorubicin (DOXO) prodrugs that incorporate the peptide linker Ala-Leu-Ala-Leu that serves as a substrate for the tumor-associated protease, cathepsin B, which is overexpressed in several solid tumors. Consequently, two albumin-binding prodrugs were synthesized [EMC-Arg-Arg-Ala-Leu-Ala-Leu-Ala-CPT (1) and EMC-Arg-Arg-Ala-Leu-Ala-Leu-DOXO (2) (EMC = 6-maleimidocaproic acid)]. Both prodrugs exhibited excellent water-solubility and bound rapidly and selectively to the cysteine-34 position of endogenous albumin. Further in vitro studies showed that the albumin-bound form of the prodrugs was cleaved specifically by cathepsin B as well as in human tumor homogenates. Major cleavage products were CPT-peptide derivatives and CPT for the CPT prodrug and H-Leu-Ala-Leu-DOXO, H-Leu-DOXO, and DOXO for the doxorubicin prodrug. In vivo, 1 was superior to free camptothecin in an HT-29 human colon xenograft model; the antitumor efficacy of prodrug 2 was comparable to that of free doxorubicin in the M-3366 mamma carcinoma xenograft model at equimolar doses.
authors: Tumor Biology Center, Breisacher Strasse 117, 79106 Freiburg, Germany.
authors: Björn
authors: B
authors: Schmid
authors: Da-Eun
authors: DE
authors: Chung
authors: André
authors: A
authors: Warnecke
authors: Iduna
authors: I
authors: Fichtner
authors: Felix
authors: F
authors: Kratz
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D001943:Breast Neoplasms / Q000188:drug therapy*; D002166:Camptothecin / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism / Q000627:therapeutic use; D002401:Cathepsin B / Q000378:metabolism*; D004317:Doxorubicin / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism / Q000627:therapeutic use; D006801:Humans; D051379:Mice; D008815:Mice, Inbred Strains; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism* / Q000627:therapeutic use*; D011355:Prodrugs / Q000138:chemical synthesis / Q000378:metabolism / Q000627:therapeutic use; D012709:Serum Albumin / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D009842:Oligopeptides; D011355:Prodrugs; D012709:Serum Albumin; C522252:maleimidohexyl-arginyl-arginyl-alanyl-leucyl-alanyl-leucyl-alanyl-camptothecin; C522253:maleimidohexyl-arginyl-arginyl-alanyl-leucyl-alanyl-leucyl-doxorubicin; D004317:Doxorubicin; D002401:Cathepsin B; D002166:Camptothecin