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PET imaging of hepatocellular carcinoma by targeting tumor-associated endothelium using [68Ga]Ga-PSMA-617

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

An Editorial to this article was published on 02 August 2022

Abstract

Objective

Hepatocellular carcinoma (HCC) is a malignant tumor associated with high morbidity and mortality rates. In many non-prostate solid tumors such as HCC, prostate-specific membrane antigens (PSMA) are overexpressed in tumor-associated endothelial cells. Therefore, the aim of this study was to evaluate the performance of [68Ga]Ga-PSMA-617 PET imaging on HCC with different animal models, including cell line-derived xenografts (CDX) and patient-derived xenografts (PDX), and to explore its mechanisms of function.

Methods

[68Ga]Ga-PSMA-617 was prepared. The expression level of PSMA in two human hepatocellular cancer cells (HepG2 and HuH-7) was evaluated, and the cellular uptakes of [68Ga]Ga-PSMA-617 were assayed. HepG2 and HuH-7 subcutaneous xenograft models, HepG2 orthotopic xenograft models, and four different groups of PDX models were prepared. Preclinical pharmacokinetics and performance of [68Ga]Ga-PSMA-617 were evaluated in different types of HCC xenografts models using small animal PET and biodistribution studies.

Results

Low PSMA expression level of HepG2 and HuH-7 cells was observed, and the cellular uptake and blocking study confirmed the non-specificity of the PSMA-targeted probe binding to HepG2 and HuH-7 cells. In the subcutaneous xenograft models, the tumor uptakes at 0.5 h were 0.76 ± 0.12%ID/g (HepG2 tumors) and 0.78 ± 0.08%ID/g (HuH-7 tumors), respectively, which were significantly higher than those of the blocking groups (0.23 ± 0.04%ID/g and 0.20 ± 0.04%ID/g, respectively). In the orthotopic xenograft models, PET images clearly displayed the tumor locations based on the preferential accumulation of [68Ga]Ga-PSMA-617 in tumor tissue versus normal liver tissue, suggesting the possibility of using [68Ga]Ga-PSMA-617 PET imaging to detect primary HCC lesions in deep tissue. In the four different groups of HCC PDX models, PET imaging with [68Ga]Ga-PSMA-617 provided clear tumor uptakes with prominent tumor-to-background contrast, further demonstrating its potential for the clinical imaging of PSMA-positive HCC lesions. The staining of tumor tissue sections with CD31- and PSMA-specific antibodies visualized the tumor-associated blood vessels and PSMA expression on endothelial cells in subcutaneous, orthotopic tissues, and PDX tissues, confirming the imaging with [68Ga]Ga-PSMA-617 might be mediated by targeting tumor associated endothelium.

Conclusion

In this study, in vivo PET on different types of HCC xenograft models illustrated high uptake within tumors, which confirmed that [68Ga]Ga-PSMA-617 PET may be a promising imaging modality for HCC by targeting tumor associated endothelium.

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Acknowledgements

We would also like to acknowledge the service provided by Beijing Novel Medical Equipment Ltd. for image acquisition.

Funding

This work was funded by the National Natural Science Foundation of China (No. 82030052).

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Authors and Affiliations

  1. Department of Nuclear Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei, Wuhan, 430022, China

    Qiaomiao Lu, Yu Long, Yongkang Gai, Qingyao Liu, Dawei Jiang & Xiaoli Lan

  2. Hubei Key Laboratory of Molecular Imaging, Hubei, Wuhan, 430022, China

    Qiaomiao Lu, Yu Long, Yongkang Gai, Qingyao Liu, Dawei Jiang & Xiaoli Lan

  3. Department of Radiology and Department of Medical Physics, University of Wisconsin–Madison, Madison, WI, 53705, USA

    Kevin Fan & Weibo Cai

  4. Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China

    Zhiwen Shen & Chidan Wan

  5. Key Laboratory of Biological Targeted Therapy of the Ministry of Education, Hubei, Wuhan, 430022, China

    Yongkang Gai, Qingyao Liu, Dawei Jiang & Xiaoli Lan

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  1. Qiaomiao Lu
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Correspondence to Chidan Wan or Xiaoli Lan.

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All experimental schemes were performed under the guidance and approved by the Institutional Animal Care and Use Committee of Tongji Medical College of Huazhong University of Science and Technology. Extensive efforts were made to ensure minimal suffering of the animals used during the study.

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Weibo Cai is a scientific advisor, stockholder, and grantee of Focus-X Therapeutics, Inc. All other authors declare no conflict of interest.

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Lu, Q., Long, Y., Fan, K. et al. PET imaging of hepatocellular carcinoma by targeting tumor-associated endothelium using [68Ga]Ga-PSMA-617. Eur J Nucl Med Mol Imaging 49, 4000–4013 (2022). https://doi.org/10.1007/s00259-022-05884-9

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