3 years ago

Targeted Cancer Therapy Using Fusion Protein of TNFα and Tumor-Associated Fibronectin-Specific Aptide

Targeted Cancer Therapy Using Fusion Protein of TNFα and Tumor-Associated Fibronectin-Specific Aptide
Daejin Kim, Sukmo Kang, Sunghyun Kim, Hyungsu Jeon, Sangyong Jon, Jin Yong Kim, Minsuk Choi
Tumor necrosis factor-α has shown potent antitumor effects in preclinical and clinical studies. However, severe side effects at less than therapeutic doses have limited its systemic delivery, prompting the need for a new strategy for targeted delivery of the protein to tumors. Here, we report a fusion protein of mouse tumor necrosis factor (TNF)-α (mTNFα) and a cancer-targeting, high-affinity aptide and investigate its therapeutic efficacy in tumor-bearing mice. A fusion protein consisting of mTNFα, a linker, and an aptide specific to extra domain B (EDB) of fibronectin (APTEDB), designated mTNFα-APTEDB, was successfully produced by expression in Escherichia coli. mTNFα-APTEDB retained specificity and affinity for its target, EDB. In mice bearing EDB-overexpressing fibrosarcomas, mTNFα-APTEDB showed greater efficacy in inhibiting tumor growth than mTNFα alone or mTNFα linked to a nonrelevant aptide, without causing an appreciable loss in body weight. Moreover, in vivo antitumor efficacy was further significantly increased by combination treatment with the chemotherapeutic drug, melphalan, suggesting a synergistic effect attributable to enhanced drug uptake into the tumor as a result of TNFα-mediated enhanced vascular permeability. These results suggest that a fusion protein of mTNFα with a cancer-targeting peptide could be a new anticancer therapeutic option for ensuring potent antitumor efficacy after systemic delivery.

Publisher URL: http://dx.doi.org/10.1021/acs.molpharmaceut.7b00520

DOI: 10.1021/acs.molpharmaceut.7b00520

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