Oncotarget

Research Papers:

An engineered TIMP2-based and enediyne-integrated fusion protein for targeting MMP-14 shows potent antitumor efficacy

Jian Xu, Xiu-Jun Liu, Liang Li, Sheng-Hua Zhang, Yi Li, Rui-Juan Gao and Yong-Su Zhen _

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Oncotarget. 2015; 6:26322-26334. https://doi.org/10.18632/oncotarget.4709

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Abstract

Jian Xu1, Xiu-Jun Liu1, Liang Li1, Sheng-Hua Zhang1, Yi Li1, Rui-Juan Gao1, Yong-Su Zhen1

1Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China

Correspondence to:

Yong-Su Zhen, e-mail: [email protected]

Keywords: MMP-14, TIMP2, fusion protein, targeted therapeutics, antitumor efficacy

Received: April 30, 2015     Accepted: July 08, 2015     Published: July 20, 2015

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.


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