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Homodimeric peptide radiotracer [68Ga]Ga-NOTA-(TMVP1)2 for VEGFR-3 imaging of cervical cancer patients

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Abstract

Purpose

Vascular endothelial growth factor receptor 3 (VEGFR-3) plays a critical role in tumor lymphangiogenesis and metastasis, holding promise as a promising therapeutic target for solid tumors. TMVP1 (LARGR) is a 5-amino acid peptide previously identified in our laboratory from bacterial peptide display system that specifically targets VEGFR-3. Radiolabeled TMVP1 can be used for non-invasive imaging of VEGFR-3 expressing tumors. Homodimeric peptides have better targeting ability than monomeric peptides, and it is worth exploring whether homodimers of TMVP1 ((TMVP1)2) can achieve better imaging effects. This study aimed to explore the peptide properties and tumor assessment value of [68Ga]Ga-labeled (TMVP1)2.

Methods

In this study, we developed a TMVP1 homodimer that was conjugated with 1,4,7-triazacyclononane-N, N′, N″-triacetic acid (NOTA) via tetraethyleneglycol (PEG4) and triglyicine (Gly3) spacer, and labeled with 68Ga, to construct [68Ga]Ga-NOTA-(TMVP1)2. Binding of VEGFR-3 by TMVP1 and (TMVP1)2, respectively, was modeled by molecular docking. The affinity of [68Ga]Ga-NOTA-(TMVP1)2 for VEGFR-3 and its ability to bind to cells were evaluated. MicroPET imaging and biodistribution studies of [68Ga]Ga-NOTA-(TMVP1)2 were performed in subcutaneous C33A cervical cancer xenografts. Five healthy volunteers and eight patients with cervical cancer underwent whole-body PET/CT acquisition 30–45 min after intravenous injection of [68Ga]Ga-NOTA-(TMVP1)2.

Results

Both molecular docking and cellular experiments showed that homodimeric TMVP1 had a higher affinity for VEGFR-3 than monomeric TMVP1. [68Ga]Ga-NOTA-(TMVP1)2 was excreted mainly through the renal route and partly through the liver route. In mice bearing C33A xenografts, [68Ga]Ga-NOTA-(TMVP1)2 specifically localized in the tumor (2.32 ± 0.10% ID/g). Pretreatment of C33A xenograft mice with the unlabeled peptide NOTA-(TMVP1)2 reduced the enrichment of [68Ga]Ga-NOTA-(TMVP1)2 in tumors (0.58 ± 0.01% ID/g). [68Ga]Ga-NOTA-(TMVP1)2 proved to be safe in all healthy volunteers and recruited patients, with no side effects or allergies noted. In cervical cancer patients, a majority of the [18F]-FDG identified lesions (18/22, 81.8%) showed moderate to high signal intensity on [68Ga]Ga-NOTA-(TMVP1)2. SUVmax and SUVmean were 2.32 ± 0.77 and 1.61 ± 0.48, respectively. With normal muscle (gluteus maximus) as background, tumor-to-background ratios were 3.49 ± 1.32 and 3.95 ± 1.64 based on SUVmax and SUVmean, respectively.

Conclusion

The favorable characterizations of [68Ga]Ga-NOTA-(TMVP1)2 such as convenient synthesis, high specific activity, and high tumor uptake enable the evaluation of VEGFR-3 in cervical cancer patients and warrant further clinical studies.

Trial registration

ChiCTR-DOD-17012458. Registered August 23, 2017 (retrospectively registered).

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Data availability

The data supporting this study’s findings are available from the corresponding author, upon reasonable request.

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Funding

The authors acknowledge financial support by the National Natural Science Foundation of China (22104040, 82172717, 81802608, and 82272628) and the co-operation Research Plan of Medical Science and Technology of Henan Province (LHGJ20220415).

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Author notes

  1. Xi Chen and Zhenzhong Zhang these authors made equal contributions to this work.

Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430034, China

    Xi Chen, Zhenzhong Zhang, Ying Zhou, Rui Wei, Ding Ma, Jun Dai, Fei Li & Ling Xi

  2. National Clinical Research Centre for Obstetrics and Gynecology, Cancer Biology Research Centre (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430034, China

    Xi Chen, Zhenzhong Zhang, Ying Zhou, Rui Wei, Ding Ma, Jun Dai, Fei Li & Ling Xi

  3. Department of Obstetrics and Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, China

    Xi Chen & Ruixia Guo

  4. Department of Gynecologic Oncology, Henan Provincial Cancer Hospital, Affiliated Tumor Hospital of Zhengzhou University, Zhengzhou, Henan, China

    Zhenzhong Zhang

  5. Department of Nuclear Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

    Ling Wang, Jingjing Zhang, Jiong Cai, Yonghong Dang & Fang Li

  6. Department of Diagnostic Radiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore

    Jingjing Zhang & Tianzhi Zhao

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

    Jingjing Zhang & Tianzhi Zhao

  8. Nanomedicine Translational Research Program, NUS Center for Nanomedicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore

    Jingjing Zhang & Tianzhi Zhao

  9. State Key Laboratory of Biogeology and Environmental Geology, Faculty of Materials Science and Chemistry, China University of Geosciences, Wuhan, 430074, China

    Rui Liu, Xiaoding Lou & Fan Xia

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  1. Xi Chen
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  2. Zhenzhong Zhang
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  3. Ling Wang
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  5. Tianzhi Zhao
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  15. Fang Li
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Corresponding authors

Correspondence to Jun Dai, Fei Li or Ling Xi.

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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. Animal care and handling procedures were in agreement with the guidelines evaluated and approved by the Ethics Committee of Tongji Medical College Huazhong University of Science and Technology.

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Chen, X., Zhang, Z., Wang, L. et al. Homodimeric peptide radiotracer [68Ga]Ga-NOTA-(TMVP1)2 for VEGFR-3 imaging of cervical cancer patients. Eur J Nucl Med Mol Imaging (2024). https://doi.org/10.1007/s00259-024-06661-6

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