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. 2023 Feb 22:10:291-301.
doi: 10.2147/JHC.S390939. eCollection 2023.

PET Imaging of Hepatocellular Carcinoma Using ZD2-(68Ga-NOTA)

Olga Sergeeva  1 , Yifan Zhang  1 , Songqi Gao  2 , E Ricky Chan  3 , Maxim Sergeev  4 , Renuka Iyer  5 , Sandra Sexton  5 , Norbert Avril  4 , Zheng-Rong Lu  2 , Zhenghong Lee  1
Affiliations

PET Imaging of Hepatocellular Carcinoma Using ZD2-(68Ga-NOTA)

Olga Sergeeva et al. J Hepatocell Carcinoma. .

Abstract

Purpose: We tested a recently developed short peptide radioligand for PET imaging of hepatocellular carcinoma (HCC) by targeting an oncoprotein, extra-domain B fibronectin (EDB-FN) in the tumor microenvironment.

Methods: The radioligand consists of a small linear peptide ZD2 with 68Ga-NOTA chelator, and specifically binds to EDB-FN. PET images were acquired dynamically for 1 hour after intravenously (i.v.) injecting 37 MBq (1.0 mCi) of the radioligand into the woodchuck model of naturally occurring HCC. Woodchuck HCC originated from chronic viral hepatitis infection, which recapitulates the corresponding human primary liver cancer. The animals were euthanized post-imaging for tissue collection and validation.

Results: For ZD2 avid liver tumors, the radioligand accumulation plateaued a few minutes after injection, while the liver background uptake stabilized 20 min post-injection. The status of EDB-FN in woodchuck HCC was confirmed by histology and validated by PCR and western blocking.

Conclusion: We have showed the viability of using the ZD2 short peptide radioligand targeting EDB-FN in liver tumor tissue for PET imaging of HCC, which can potentially impact the clinical care for HCC patients.

Keywords: EDB fibronectin; peptide ligand; positron emission tomography; woodchuck model.

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Conflict of interest statement

Dr Songqi Gao reports a patent WO2020150617A8 licensed to CWRU. Dr Zheng-Rong Lu reports a patent US Patent App. 17/424,104 pending to Molecular Theranostics, LLC. The authors report no other conflicts of interest in this work.

Figures

Figure 1
Figure 1
TCGA data showing higher EDB-FN expression in HCC compared with that in the liver (A), and the inverse correlation of EDB-FN expression in HCC with patient survival (B).
Figure 2
Figure 2
Validation results indicating highly expressed EDB-FN in the woodchuck HCC. (A) Higher EDB-FN expression in the woodchuck HCC compared to the surrounding hepatic tissues analyzed from the customized microarray data; Higher EDB-FN expression in HCC compared to the surrounding liver determined in harvested tissue samples from the woodchucks carrying HCC with RT-PCR (B) and Western blotting (C).
Figure 3
Figure 3
PET imaging of ZD2-[68Ga-NOTA] with woodchuck (#1701). (A) PET/CT overlays of coronal (left) and axial (right) cuts showing uptake in one HCC (T1 for tumor 1) with L for liver, S for stomach, and H for heart; (B) region-based uptake (in SUVs) as time activity curves for these organs.
Figure 4
Figure 4
Histology analysis. (A) Immunofluorescence staining of woodchuck frozen sections (upper: liver, lower: tumor) with G4 anti-EDB-FN monoclonal antibody (red). While substantial EDB-FN was stained in the extracellular matrix of the HCC, normal liver was not stained; (B) Specific binding of ZD2 peptide to EDB-FN in woodchuck HCC was observed for strong binding of ZD2-Cy5.5 (red) in tumor tissues while little fluorescence staining was observed for the adjacent woodchuck HCC sections pre-incubated with G4 antibody and followed by ZD2-Cy5.5, indicating blockage of ZD2-Cy5.5 binding by G4 antibody (blocking).
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