title: 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.
authors.affiliation: Bristol-Myers Squibb Research and Development, PO Box 5400, Princeton, NJ 08543, USA. zilun.hu@bms.com
authors.forename: Zilun
authors.initials: Z
authors.lastname: Hu
authors.forename: Xiangjun
authors.initials: X
authors.lastname: Jiang
authors.forename: Charles F
authors.initials: CF
authors.lastname: Albright
authors.forename: Nilsa
authors.initials: N
authors.lastname: Graciani
authors.forename: Eddy
authors.initials: E
authors.lastname: Yue
authors.forename: Mingzhu
authors.initials: M
authors.lastname: Zhang
authors.forename: Shu-Yun
authors.initials: SY
authors.lastname: Zhang
authors.forename: Robert
authors.initials: R
authors.lastname: Bruckner
authors.forename: Melody
authors.initials: M
authors.lastname: Diamond
authors.forename: Randine
authors.initials: R
authors.lastname: Dowling
authors.forename: Maria
authors.initials: M
authors.lastname: Rafalski
authors.forename: Swamy
authors.initials: S
authors.lastname: Yeleswaram
authors.forename: George L
authors.initials: GL
authors.lastname: Trainor
authors.forename: Steven P
authors.initials: SP
authors.lastname: Seitz
authors.forename: Wei
authors.initials: W
authors.lastname: Han
mesh_terms: 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
chemical_list: D000970:Antineoplastic Agents; D011355:Prodrugs; D004317:Doxorubicin; D020782:Matrix Metalloproteinases