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Therapeutic efficacy and imaging assessment of the HER2-targeting chemotherapy drug ZHER2:V2-pemetrexed in lung adenocarcinoma Xenografts

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Summary

Chemotherapy has always been the first therapeutic option for patients with advanced non-small cell lung cancer (NSCLC) with untreatable oncogenic mutations. However, chemotherapy has demonstrated limited success and is associated with severe side effects. This research aimed to investigate the antitumor efficacy and cytotoxic safety of the conjugate ZHER2:V2-pemetrexed, a novel targeted chemotherapeutic drug. In this context, human epidermal growth factor receptor 2 (HER2) + A549 lung xenografts were treated using ZHER2:V2-pemetrexed, pemetrexed or physiological saline. Therapeutic efficacy was monitored by single photon emission computed tomography (SPECT) imaging using the 99mTc-labeled ZHER2:V2-pemetrexed conjugate and further confirmed by performing apoptosis assays using flow cytometry analysis and hematoxylin-eosin (H&E) staining. To evaluate the expression of HER2 in tumor tissues, immunohistochemistry was performed, accompanied by quantitative analysis using flow cytometry. A toxicological evaluation was also conducted. Imaging with 99mTc-ZHER2:V2-pemetrexed demonstrated that in HER2+ A549 models, ZHER2:V2-pemetrexed showed better antineoplastic effects than pemetrexed. Compared with pemetrexed, the results from the pathological and flow cytometry analyses also revealed that ZHER2:V2-pemetrexed exhibits high antitumor activity against A549 tumors, inducing necrosis, apoptosis and cell cycle arrest. In addition, the clinical signs of toxicity in the ZHER2:V2-pemetrexed treated group were reduced compared with those in the pemetrexed treated group. These data revealed that the ZHER2:V2-pemetrexed conjugate encompasses promising targeted antitumor activity against HER2-positive lung adenocarcinoma, with reduced side effects compared with pemetrexed. Thus, the ZHER2:V2-pemetrexed conjugate may serve as a novel molecular agent with tremendous clinical breakthrough potential in the diagnosis and treatment of HER2-positive lung adenocarcinoma.

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Acknowledgments

This study was supported by funds from the National Natural Science Foundation of China (NSFC) project (NO. 81571702). The authors would like to acknowledge the assistance of all coworkers involved in the study.

Funding

This study was supported by funds from the National Natural Science Foundation of China (NSFC) project (NO. 81571702).

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Authors and Affiliations

  1. Department of Nuclear Medicine, The Fourth Hospital of Hebei Medical University, Jiankang Road, Shijiazhuang, 050011, Hebei Province, China

    Jingya Han, Xinming Zhao, Tuo Ma, Tiancheng Hao, Jiahui Liu, Zhaoqi Zhang, Jingmian Zhang & Jianfang Wang

  2. Department of Oncology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, 050011, China

    Yan Zhao

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  1. Jingya Han
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  2. Yan Zhao
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  3. Xinming Zhao
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Contributions

All authors contributed to the study conception and design. Material preparation, data collection, and analyses were performed by Jingya Han, Tiancheng Hao, Tuo Ma and Jiahui Liu. The first draft of the manuscript was written by Jingya Han. The manuscript was reviewed by Xinming Zhao and Yan Zhao. All authors commented on previous versions of the manuscript. All authors have read and approved the final manuscript.

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Correspondence to Xinming Zhao.

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This article does not contain any studies with human participants performed by any of the authors. All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in this study involving animals were in accordance with the ethical standards of the Laboratory Animal Ethical Committee of the Fourth Hospital Hebei Medical University (SCXK[JI] 2013–0051).

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Han, J., Zhao, Y., Zhao, X. et al. Therapeutic efficacy and imaging assessment of the HER2-targeting chemotherapy drug ZHER2:V2-pemetrexed in lung adenocarcinoma Xenografts. Invest New Drugs 38, 1031–1043 (2020). https://doi.org/10.1007/s10637-019-00876-3

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