Recombinant EGFR/MMP-2 bi-targeted fusion protein markedly binding to non-small-cell lung carcinoma and exerting potent therapeutic efficacy. (December 2017)

• Record Type: Journal Article
• Authors: Xu, Jian; Du, Yue; Liu, Xiu-Jun; Zhu, Bing-Yan; Zhang, Sheng-Hua; Li, Liang; Li, Yi; Wang, Xiao-Fei; Shan, Chuan-Kun; Wang, Rui-Qi; Zhen, Yong-Su
• Is Part Of: Pharmacological research. Volume 126(2017:Dec.)
• Page Start: 66
• Page End: 76
• Publication Date: 2017-12
• Subjects: EGFR epidermal growth factor receptor -- MMPs matrix metalloproteinases -- Ec EGF derived oligopeptide -- TIMP2 tissue inhibitor of matrix metalloproteinase 2 -- LDM lidamycin -- LDP lidamycin apoprotein -- AE active enediyne -- NSCLC non-small-cell lung carcinoma -- ADC antibody-drug conjugate -- ECM extracellular matrix -- EMT epithelial-mesenchymal transition; Fusion protein -- Delivery carrier -- EGFR/MMP-2 bi-targeted -- Enediyne -- Therapeutic efficacy; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2017.04.001
• Languages: English
• ISSNs: 1043-6618

Abstract

Graphical abstract: Abstract: Overexpression of EGFR and MMP-2 plays an essential role in the initiation and progression of non-small-cell lung carcinoma (NSCLC). In this study, a novel format of EGFR/MMP-2 bi-targeted fusion protein Ec-LDP-TIMP2 and its enediyne-integrated analogue Ec-LDP(AE)-TIMP2 have been prepared by genetic engineering and molecular reconstitution. The Ec-LDP(AE)-TIMP2 comprises endogenous inhibitor of matrix metalloproteinase 2 (TIMP2), EGF-derived oligopeptide (Ec), lidamycin apoprotein (LDP), and the extremely potent cytotoxic enediyne (AE). By tissue microarray, Ec-LDP-TIMP2 showed high binding intensity and selectivity to human NSCLC specimens as compared with the matched non-cancerous tissues. By in vivo imaging, Ec-LDP-TIMP2 displayed prominent tumor-specific distribution in human NSCLC H460 xenograft. Particularly, Ec-LDP(AE)-TIMP2 inhibited tumor growth of H460 xenograft in athymic mice more striking. At doses of 0.2 and 0.4 mg/kg, Ec-LDP(AE)-TIMP2 suppressed tumor growth by 74% and 89%, respectively. No histopathological changes were found in various organs of treated animals, suggesting that the effective dosage was tolerated. In summary, the ligand-based and enediyne-integrated fusion protein displaying extremely potent cytotoxicity might be highly effective for NSCLC therapy and useful as a carrier for drug delivery.