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PDGFRβ-antagonistic affibody mediated tumor-targeted TNFα for enhanced radiotherapy in lung cancer
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  • Xiaohui Tang,
  • Jie Chen,
  • Zhenxiong Zhao,
  • Jie Liu,
  • Ranfei Yu,
  • Kunlong Zhao,
  • Fei Wang,
  • Yang Li,
  • Baoqing Tian,
  • Dandan Yuan,
  • Qin Wei,
  • Yuguo Liu,
  • Zhong Feng Gao,
  • Qing Fan
Xiaohui Tang
Shandong Cancer Hospital and Institute Shandong First Medical University and Shandong Academy of Medical Sciences
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Jie Chen
West China Hospital of Sichuan University
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Zhenxiong Zhao
Taizhou Central Hospital
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Jie Liu
Shandong Cancer Hospital and Institute Shandong First Medical University and Shandong Academy of Medical Sciences
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Ranfei Yu
Shandong Cancer Hospital and Institute Shandong First Medical University and Shandong Academy of Medical Sciences
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Kunlong Zhao
Shandong Cancer Hospital and Institute Shandong First Medical University and Shandong Academy of Medical Sciences
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Fei Wang
Shandong Cancer Hospital and Institute Shandong First Medical University and Shandong Academy of Medical Sciences
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Yang Li
Shandong Cancer Hospital and Institute Shandong First Medical University and Shandong Academy of Medical Sciences
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Baoqing Tian
Shandong Cancer Hospital and Institute Shandong First Medical University and Shandong Academy of Medical Sciences
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Dandan Yuan
Shandong Cancer Hospital and Institute Shandong First Medical University and Shandong Academy of Medical Sciences
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Qin Wei
University of Jinan
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Yuguo Liu
Shandong Cancer Hospital and Institute Shandong First Medical University and Shandong Academy of Medical Sciences
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Zhong Feng Gao
University of Jinan

Corresponding Author:[email protected]

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Qing Fan
Shandong Cancer Hospital and Institute Shandong First Medical University and Shandong Academy of Medical Sciences
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Abstract

The morbidity and mortality of lung cancer are still the highest among all malignant tumors. Radiotherapy plays an important role in clinical treatment of lung cancer. But the effect of radiotherapy is not ideal due to the radiation resistance of tumor tissues. Abnormalities in tumor vascular structure and function affect blood perfusion and oxygen transport is impeded, making tumor microenvironment hypoxic. Tumor hypoxia is the major cause of radiotherapy resistance. By promoting tumor vessels normalization and enhancing vascular transport function, tumor hypoxia can be relieved to reduce radiotherapy resistance and increase tumor radiotherapy sensitivity. In our previous study, a pericytes-targeted tumor necrosis factor alpha (named Z-TNFα) was firstly constructed and produced by genetically fusing the platelet-derived growth factor receptor β (PDGFRβ)-antagonistic affibody (ZPDGFRβ) to the TNFα, and the Z-TNFα induced normalization of tumor vessels and improved the delivery of doxorubicin, enhancing tumor chemotherapy. In this study, the tumor vessel normalization effect of Z-TNFα in lung cancer was further clarified. Moreover, the tumor hypoxia improvement and radiosensitizing effect of Z-TNFα were emphatically explored in vivo. Inspiring, Z-TNFα specifically accumulated in Lewis lung carcinoma tumor graft, and relieved tumor hypoxia as well as inhibited HIF-1α expression. As expected, Z-TNFα significantly increased the effect of radiotherapy in mice bearing Lewis lung carcinoma tumor graft. In conclusion, these results demonstrated that Z-TNFα is also a promising radiosensitizer for lung cancer radiotherapy.