Intensive fibrosarcoma-binding capability of the reconstituted analog and its antitumor activity

• Published in: Drug delivery Vol. 25; no. 1; pp. 102 - 111
• Main Authors: Xu, Jian, Du, Yue, Liu, Wen-Juan, Li, Liang, Li, Yi, Wang, Xiao-Fei, Yi, Hong-Fei, Shan, Chuan-Kun, Xia, Gui-Min, Liu, Xiu-Jun, Zhen, Yong-Su
• Format: Journal Article
• Language: English
• Published: England Taylor & Francis 01.01.2018; Taylor & Francis Ltd; Taylor & Francis Group
• Subjects: A549 Cells; Angiogenesis; Animals; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; binding capability; Biotechnology; Cancer therapies; Cell cycle; Cell Cycle Checkpoints - drug effects; Cell Line, Tumor; Cell Movement - drug effects; Cell Proliferation - drug effects; Chemotherapy; Cytotoxicity; Drug delivery; Drugs; evaluation; Extracellular matrix; Fibrosarcoma; Fibrosarcoma - drug therapy; Fibrosarcoma - metabolism; G2 Phase Cell Cycle Checkpoints - drug effects; Humans; Kinases; Matrix Metalloproteinases - metabolism; Metastasis; Mice; Mice, Inbred BALB C; Mice, Nude; Proteins; Tissue Inhibitor of Metalloproteinase-2 - metabolism; treatment efficacy; Tumors; Beijing China; China; evaluation; Drug delivery; binding capability; fibrosarcoma; treatment efficacy
• ISSN: 1071-7544; 1521-0464
• DOI: 10.1080/10717544.2017.1410261

Fibrosarcomas are highly aggressive malignant tumors. It is urgently needed to explore targeted drugs and modalities for more effective therapy. Matrix metalloproteinases (MMPs) play important roles in tumor progression and metastasis, while several MMPs are highly expressed in fibrosarcomas. In addition, tissue inhibitor of metalloproteinase 2 (TIMP2) displays specific interaction with MMPs. Therefore, TIMP2 may play an active role in the development of fibrosarcoma-targeting agents. In the current study, a TIMP2-based recombinant protein LT and its enediyne-integrated analog LTE were prepared; furthermore, the fibrosarcoma-binding intensity and antitumor activity were investigated. As shown, intense and selective binding capability of the protein LT to human fibrosarcoma specimens was confirmed by tissue microarray. Moreover, LTE, the enediyne-integrated analog of LT, exerted highly potent cytotoxicity to fibrosarcoma HT1080 cells, induced apoptosis, and caused G2/M arrest. LTE at 0.1 nM markedly suppressed the migration and invasion of HT1080 cells. LTE at tolerated dose of 0.6 mg/kg inhibited the tumor growth of fibrosarcoma xenograft in athymic mice. The study provides evidence that the TIMP2-based reconstituted analog LTE may be useful as a targeted drug for fibrosarcome therapy.