Discovery of matrix metalloproteases selective and activated peptide-doxorubicin prodrugs as anti-tumor agents

被引：11

作者：

Hu, Zilun ^{[1
]}

Jiang, Xiangjun ^{[1
]}

Albright, Charles F. ^{[1
]}

Graciani, Nilsa ^{[1
]}

Yue, Eddy ^{[1
]}

Zhang, Mingzhu ^{[1
]}

Zhang, Shu-Yun ^{[1
]}

Bruckner, Robert ^{[1
]}

Diamond, Melody ^{[1
]}

Dowling, Randine ^{[1
]}

Rafalski, Maria ^{[1
]}

Yeleswaram, Swamy ^{[1
]}

Trainor, George L. ^{[1
]}

Seitz, Steven P. ^{[1
]}

Han, Wei ^{[1
]}

机构：

[1] Bristol Myers Squibb Res & Dev, Princeton, NJ 08543 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2010年 / 20卷 / 03期

关键词：

Doxorubicin; Matrix metalloproteases; Prodrug; TOXICITY; EFFICACY; CANCER;

D O I：

10.1016/j.bmcl.2009.12.084

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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. (C) 2009 Elsevier Ltd. All rights reserved.

引用

页码：853 / 856

页数：4

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