A new approach for the treatment of malignant melanoma: enhanced antitumor efficacy of an albumin-binding doxorubicin prodrug that is cleaved by matrix metalloproteinase 2.
The progression of malignant melanoma is characterized by overexpression of a number of matrix metalloproteinases (MMPs), especially MMP-2, which play a critical role in the degradation of basement membranes and the extracellular matrix. Consequently, we assessed a drug targeting strategy in which the protease activity of MMP-2 is exploited to release an anticancer agent from a macromolecular carrier, i.e., circulating albumin. For this purpose, a water-soluble maleimide derivative of doxorubicin (1) incorporating a MMP-2 specific peptide sequence (Gly-Pro-Leu-Gly-Ile-Ala-Gly-Gln) was developed that binds rapidly and selectively to the cysteine-34 position of circulating albumin. The albumin-bound form of 1 was efficiently and specifically cleaved by MMP-2 liberating a doxorubicin tetrapeptide (Ile-Ala-Gly-Gln-DOXO) and subsequently doxorubicin. In vivo, 1 was superior to the parent compound doxorubicin in the A375 human melanoma xenograft, which is characterized by a high expression of MMP-2.
Mansour
Ahmed M
AM
Tumor Biology Center, Breisacher Strasse 117, 79106 Freiburg, Germany.
Drevs
Joachim
J
Esser
Norbert
N
Hamada
Farid M
FM
Badary
Osama A
OA
Unger
Clemens
C
Fichtner
Iduna
I
Kratz
Felix
F
D000418:Albumins / Q000493:pharmacokinetics*; D000903:Antibiotics, Antineoplastic / Q000493:pharmacokinetics* / Q000494:pharmacology; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D008301:Maleimides / Q000493:pharmacokinetics; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D008545:Melanoma / Q000188:drug therapy* / Q000201:enzymology*; D009842:Oligopeptides / Q000493:pharmacokinetics*; D011355:Prodrugs / Q000493:pharmacokinetics*; D014407:Tumor Cells, Cultured
D000418:Albumins; D000903:Antibiotics, Antineoplastic; D008301:Maleimides; D009842:Oligopeptides; D011355:Prodrugs; D004317:Doxorubicin; D020778:Matrix Metalloproteinase 2