title: An engineered TIMP2-based and enediyne-integrated fusion protein for targeting MMP-14 shows potent antitumor efficacy.
abstract: Recent studies have shown that MMP-14 is highly expressed in a panel of human solid tumors and poses as a potential molecular target for anticancer drugs. Currently, major strategies for targeted therapeutics have mainly focused on the use of antibody or ligand-based agents. For seeking an alternative approach, it is of interest to employ endogenous proteins as drug delivery carriers. Considering the facts that TIMP2, the tissue inhibitor of metalloproteinase 2, shows specific interaction with MMP-14 and that Lidamycin (LDM), an extremely potent cytotoxic antitumor antibiotic, consists of an apoprotein (LDP) and a highly active enediyne (AE); we designed and prepared a TIMP2-based and enediyne-integrated fusion protein LDP(AE)-TIMP2 by DNA recombination and molecular reconstitution consecutively. Furthermore, the MMP-14 binding attributes of the active fusion protein were determined and its therapeutic efficacy against human esophageal carcinoma KYSE150 xenograft and human fibrosarcoma HT1080 xenograft models in nude mice was investigated. It is suggested that TIMP2, the endogenous and MMP-14 binding protein, might serve as a guided carrier for targeted therapeutics.
authors: Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
authors: Jian
authors: J
authors: Xu
authors: Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
authors: Xiu-Jun
authors: XJ
authors: Liu
authors: Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
authors: Liang
authors: L
authors: Li
authors: Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
authors: Sheng-Hua
authors: SH
authors: Zhang
authors: Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
authors: Yi
authors: Y
authors: Li
authors: Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
authors: Rui-Juan
authors: RJ
authors: Gao
authors: Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
authors: Yong-Su
authors: YS
authors: Zhen
mesh_terms: D000617:Aminoglycosides / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology*; D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D053281:Enediynes / Q000494:pharmacology*; D004938:Esophageal Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors / Q000494:pharmacology*; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D018919:Neovascularization, Physiologic / Q000187:drug effects; D011485:Protein Binding; D015202:Protein Engineering; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D013997:Time Factors; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology*; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000617:Aminoglycosides; D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D053281:Enediynes; D061965:Matrix Metalloproteinase Inhibitors; D011993:Recombinant Fusion Proteins; C058024:C 1027; D019716:Tissue Inhibitor of Metalloproteinase-2; C507086:MMP14 protein, human; D053511:Matrix Metalloproteinase 14
keywords: MMP-14; TIMP2; antitumor efficacy; fusion protein; targeted therapeutics