Discovery of matrix metalloproteases selective and activated peptide-doxorubicin prodrugs as anti-tumor agents.
Bioorganic & medicinal chemistry letters 2010 Jan 4; In press
Hu Z, Jiang X, Albright C CF, Graciani N, Yue E, Zhang M, Zhang S SY, Bruckner R, Diamond M, Dowling R, Rafalski M, Yeleswaram S, Trainor G GL, Seitz S SP, Han W
Bristol-Myers Squibb Research and Development, PO Box 5400, Princeton, NJ 08543, USA.
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.
Keywords: MMP doxorubicin