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

Abstract 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.