Discovery of matrix metalloproteases selective and activated peptide-doxorubicin prodrugs as anti-tumor agents.
To selectively target doxorubicin (Dox) to tumor tissue and thereby improve the therapeutic index and/or efficacy of Dox, matrix metalloproteinases (MMP) activated peptide-Dox prodrugs were designed and synthesized by coupling MMP-cleavable peptides to Dox. Preferred conjugates were good substrates for MMPs, poor substrates for neprilysin, an off-target proteinase, and stable in blood ex vivo. When administered to mice with HT1080 xenografts, conjugates, such as 19, preferentially released Dox in tumor relative to heart tissue and prevented tumor growth with less marrow toxicity than Dox.
Hu
Zilun
Z
Bristol-Myers Squibb Research and Development, PO Box 5400, Princeton, NJ 08543, USA. zilun.hu@bms.com
Jiang
Xiangjun
X
Albright
Charles F
CF
Graciani
Nilsa
N
Yue
Eddy
E
Zhang
Mingzhu
M
Zhang
Shu-Yun
SY
Bruckner
Robert
R
Diamond
Melody
M
Dowling
Randine
R
Rafalski
Maria
M
Yeleswaram
Swamy
S
Trainor
George L
GL
Seitz
Steven P
SP
Han
Wei
W
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000494:pharmacology; D055808:Drug Discovery / Q000379:methods; D006801:Humans; D020782:Matrix Metalloproteinases / Q000737:chemistry* / Q000494:pharmacology; D051379:Mice; D011355:Prodrugs / Q000737:chemistry* / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays / Q000379:methods
D000970:Antineoplastic Agents; D011355:Prodrugs; D004317:Doxorubicin; D020782:Matrix Metalloproteinases