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Development of [177Lu]Lu-LNC1010 for peptide receptor radionuclide therapy of nasopharyngeal carcinoma

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European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

Abstract

Purpose

Somatostatin Receptor 2 (SSTR2)-targeted radiopharmaceutical [68Ga]Ga-DOTATATE has potential advantages in the diagnosis of nasopharyngeal carcinoma (NPC). This study introduces a novel long-lasting SSTR2 analogue, LNC1010, based on DOTATATE, a truncated Evans blue-binding moiety, and a polyethylene-glycol linker. We hypothesised that peptide receptor radionuclide therapy (PRRT) is more effective with [177Lu]Lu-LNC1010 than with [177Lu]Lu-DOTATATE in treating metastatic NPC.

Methods

We assessed binding characteristics of LNC1010 in vitro using C666-1 NPC cells and in-vivo pharmacokinetics of [68Ga]Ga/[177Lu]Lu-LNC1010 in C666-1 NPC xenografts via PET and SPECT imaging, biodistribution studies, and PRRT, and compared them with [68Ga]Ga/[177Lu] Lu-labelled DOTATATE. Furthermore, a proof-of-concept approach for imaging and therapy was conducted in a patient with metastatic NPC.

Results

LNC1010 exhibited strong uptake and specific affinity for SSTR2 in C666-1 NPC cells. PET and SPECT imaging demonstrated higher uptake and longer tumour retention of [68Ga]Ga/[177Lu]Lu-LNC1010 than [68Ga]Ga/[177Lu]Lu-DOTATATE in C666-1 NPC xenografts, indicating its suitability for PRRT applications in NPCs. Biodistribution studies confirmed the higher uptake and prolonged retention of [177Lu]Lu-LNC1010 than [177Lu]Lu-DOTATATE. In preclinical PRRT studies, [177Lu]Lu-LNC1010 showed greater inhibition of tumour growth in C666-1 NPC xenografts than [177Lu]Lu-DOTATATE. In a subsequent pilot clinical study, PRRT with [177Lu]Lu-LNC1010 achieved favourable therapeutic and negligible side effects in a patient with metastatic NPC.

Conclusion

[177Lu]Lu-LNC1010 demonstrated increased tumour uptake and prolonged retention in SSTR2-positive NPCs, with superior anti-tumour efficacy to that of [177Lu]Lu-DOTATATE in preclinical studies. These findings suggest that PRRT with [177Lu]Lu-LNC1010 is a promising treatment for advanced NPC, extending the clinical scope of PRRT beyond neuroendocrine tumours.

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Data availability

Data generated or analysed during the study are available from the corresponding author by request.

Code availability

Not applicable.

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Funding

This work was funded by National Natural Science Foundation of China (Grant number 82071961), Key Scientific Research Program for Yong Scholars in Fujian (2021ZQNZD016), Fujian Natural Science Foundation for Distinguished Yong Scholars (2022J01310623/2022D005), the National University of Singapore (NUHSRO/2020/133/Startup/08, NUHSRO/2023/008/NUSMed/TCE/LOA, NUHSRO/2021/034/TRP/09/Nanomedicine), National Medical Research Council (MOH-001388-00, CG21APR1005), Singapore Ministry of Education (MOE-000387-00), and National Research Foundation (NRF-000352-00).

Author information

Author notes

  1. Jianhao Chen, Yizhen Pang and Xiyi Liao contributed equally to this work.

Authors and Affiliations

  1. Department of Nuclear Medicine and Minnan PET Center, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China

    Jianhao Chen, Yizhen Pang, Yangfan Zhou, Hua Wu, Liang Zhao & Haojun Chen

  2. Department of Radiation Oncology, Xiamen Cancer Center, Xiamen Key Laboratory of Radiation Oncology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China

    Jianhao Chen, Yizhen Pang, Xiyi Liao, Yangfan Zhou, Qin Lin & Liang Zhao

  3. Departments of Diagnostic Radiology, Surgery, Chemical and Biomolecular Engineering, and Biomedical Engineering, Yong Loo Lin School of Medicine and College of Design and Engineering, National University of Singapore, Singapore, Singapore

    Yizhen Pang, Jingjing Zhang, Xiaoyuan Chen & Liang Zhao

  4. Clinical Imaging Research Centre, Centre for Translational Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore

    Yizhen Pang, Jingjing Zhang, Xiaoyuan Chen & Liang Zhao

  5. Nanomedicine Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore

    Yizhen Pang, Jingjing Zhang, Xiaoyuan Chen & Liang Zhao

  6. Institute of Molecular and Cell Biology, Agency for Science, Technology, and Research (A*STAR), 61 Biopolis Drive, Proteos, Singapore, 138673, Singapore

    Yizhen Pang, Jingjing Zhang, Xiaoyuan Chen & Liang Zhao

  7. Laboratory of Xiamen Cancer Hospital, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China

    Qicong Luo

  8. Department of Nuclear Medicine, The First Affiliated Hospital of Naval Military Medical University (Shanghai Changhai Hospital), Shanghai, China

    Changjing Zuo

Authors
  1. Jianhao Chen
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  2. Yizhen Pang
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  10. Xiaoyuan Chen
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  11. Liang Zhao
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Contributions

Jianhao Chen, Yizhen Pang, and Xiyi Liao were responsible for data acquisition, literature research, and manuscript writing. Yangfan Zhou and Qichong Luo contributed to data acquisition and analysis. Hua Wu, Changjing Zuo, Jingjing Zhang, and Qin Lin provided study design and theoretical support. Xiaoyuan Chen, Liang Zhao, and Haojun Chen designed the research program and were involved in reviewing and revising the manuscript. All authors reviewed and approved the final manuscript.

Corresponding authors

Correspondence to Xiaoyuan Chen, Liang Zhao or Haojun Chen.

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Ethical approval

All procedures involving human participants were carried out in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. This article does not contain any experiments with animals.

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Informed consent was obtained from all individual participants included in the study.

Conflict of interest

X Chen is co-founder of the Yantai LNC Biotechnology. The other authors declare that they have no potential conflicts of interest.

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Chen, J., Pang, Y., Liao, X. et al. Development of [177Lu]Lu-LNC1010 for peptide receptor radionuclide therapy of nasopharyngeal carcinoma. Eur J Nucl Med Mol Imaging 52, 247–259 (2024). https://doi.org/10.1007/s00259-024-06874-9

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