Probing the cysteine-34 position of endogenous serum albumin with thiol-binding doxorubicin derivatives. Improved efficacy of an acid-sensitive doxorubicin derivative with specific albumin-binding properties compared to that of the parent compound.
We have recently proposed a macromolecular prodrug strategy for improved cancer chemotherapy based on two features (Kratz, F.; et al. J. Med. Chem 2000, 43, 1253-1256.): (a) rapid and selective binding of thiol-reactive prodrugs to the cysteine-34 position of endogenous albumin after intravenous administration and (b) release of the albumin-bound drug in the acidic environment at the tumor site due to the incorporation of an acid-sensitive bond between the drug and the carrier. To investigate this therapeutic strategy in greater depth, four (maleinimidoalkanoyl)hydrazone derivatives of doxorubicin were synthesized differing in the length of the aliphatic spacer (1, -(CH(2))(2)-; 2, -(CH(2))(3)-; 3, -(CH(2))(5)-; 4, -(CH(2))(7)-). The albumin-binding doxorubicin prodrugs, especially the (6-maleimidocaproyl)hydrazone derivative of doxorubicin (3), are rapidly and selectively bound to the cysteine-34 position of endogenous albumin. 3 was distinctly superior to the parent compound doxorubicin in three animal tumor models (RENCA, MDA-MB 435, and MCF-7) with respect to antitumor efficacy and toxicity.
Kratz
Felix
F
Tumor Biology Center, Breisacher Strasse 117, 79106 Freiburg, Germany. felix@tumorbio.uni-freiburg.de
Warnecke
André
A
Scheuermann
Karin
K
Stockmar
Cornelia
C
Schwab
Jürgen
J
Lazar
Peter
P
Drückes
Peter
P
Esser
Norbert
N
Drevs
Joachim
J
Rognan
Didier
D
Bissantz
Caterina
C
Hinderling
Caterina
C
Folkers
Gerd
G
Fichtner
Iduna
I
Unger
Clemens
C
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D002292:Carcinoma, Renal Cell / Q000188:drug therapy; D003545:Cysteine / Q000737:chemistry*; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D006835:Hydrazones / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D007680:Kidney Neoplasms / Q000188:drug therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008958:Models, Molecular; D009368:Neoplasm Transplantation; D011355:Prodrugs / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D011485:Protein Binding; D012709:Serum Albumin / Q000737:chemistry / Q000378:metabolism*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D006835:Hydrazones; D011355:Prodrugs; D012709:Serum Albumin; D004317:Doxorubicin; D003545:Cysteine