Theranostics 2018; 8(8):2217-2228. doi:10.7150/thno.24041

Research Paper

Polyamine-Targeting Gefitinib Prodrug and its Near-Infrared Fluorescent Theranostic Derivative for Monitoring Drug Delivery and Lung Cancer Therapy

Xinyu Song1,2, Xiaoyue Han2,4, Fabiao Yu2,3✉, Xiaoyu Zhang1,2, Lingxin Chen2,3✉, Changjun Lv1,3✉

1. Department of Respiratory Medicine, Binzhou Medical University Hospital, Binzhou 256603, China
2. Key Laboratory of Coastal Environmental Processes and Ecological Remediation, Yantai Institute of Coastal Zone Research, Chinese Academy of Sciences, Yantai 264003, China
3. Medicine Research Center, Institute of Molecular Medicine, Binzhou Medical University, Yantai 264003, China.
4. University of Chinese Academy of Sciences, Beijing 100049, China.

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Song X, Han X, Yu F, Zhang X, Chen L, Lv C. Polyamine-Targeting Gefitinib Prodrug and its Near-Infrared Fluorescent Theranostic Derivative for Monitoring Drug Delivery and Lung Cancer Therapy. Theranostics 2018; 8(8):2217-2228. doi:10.7150/thno.24041. Available from

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The therapy of non-small-cell lung cancer (NSCLC) is challenging because of poor prognosis. There are urgent demands for targeting anti-tumor drugs with reliable efficacy and clear pharmacokinetics.

Methods: We designed and synthesized an active tumor-targeting prodrug for the precision therapy of NSCLC. The prodrug polyamine analog Gefitinib (PPG) was derived from the conjugation between a tumor-targeting ligand polyamine analog (PA) and an epidermal growth factor receptor tyrosine kinase inhibitor Gefitinib via a cleavable disulfide linker. Furthermore, the integration of the near-infrared azo-BODIPY fluorophore into the structure of the prodrug PPG yielded an activatable fluorescent theranostics (TPG), which could be used to monitor the in real-time delivery of prodrug PPG and initiate precise medicine in vivo.

Results: PPG efficiently delivered the anti-tumor drug to cancer cells and reduced the serious side effects of the drug to normal cells, thereby increasing the potent of the anti-tumor drug. PPG was not only efficacious for killing Gefitinib-sensitive PC9 cells, but also for inhibiting the growth of Gefitinib-resistant H1650 cells. We provided a new evidence that the tumor-targeting PA ligand could inhibit the Akt pathway in H1650 cells, and had a synergistic effect with Gefitinib for anticancer efficacy. The in vivo results on nude mice bearing tumors of NSCLC cell lines demonstrated that PPG could target tumor lesions and had the expected therapeutic effects. Finally, we used TPG for fluorescent labeling of transbronchial lung biopsy (TBLB) specimens. The results indicated that TPG could provide rapid diagnosis for lung cancer within 4 h.

Conclusion: Our work had identified that PPG could be effectively used for the treatment of Gefitinib-resistance NSCLC in cells and in mice models. The theranostic TPG emerged as a promising fluorescent imaging tool for the application in the therapy and diagnosis of NSCLC.

Keywords: Lung cancer, Drug delivery, Targeting prodrug, Fluorescence theranostics, Precision medicine