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. 2017 May 26;8(43):74159-74169.
doi: 10.18632/oncotarget.18276. eCollection 2017 Sep 26.

64Cu-PSMA-617: A novel PSMA-targeted radio-tracer for PET imaging in gastric adenocarcinoma xenografted mice model

Xue-Di Han  1 , Chen Liu  1 , Fei Liu  1 , Qing-Hua Xie  1   2 , Te-Li Liu  1 , Xiao-Yi Guo  1 , Xiao-Xia Xu  1 , Xing Yang  3 , Hua Zhu  1 , Zhi Yang  1
Affiliations

64Cu-PSMA-617: A novel PSMA-targeted radio-tracer for PET imaging in gastric adenocarcinoma xenografted mice model

Xue-Di Han et al. Oncotarget. .

Abstract

Here, we report that it's feasible for imaging gastric adenocarcinoma mice model with prostate-specific membrane antigen (PSMA) targeting imaging agents, which could potentially provide an alternate and readily translational tool for managing gastric adenocarcinoma. DKFZ-PSMA-617, a PSMA targeting ligand reported recently, was chosen to be radio-labeled with nuclide 64Cu. 64Cu-PSMA-617 was radio-synthesized in high radio-chemical yield and specific activity up to 19.3 GBq/µmol. It showed good stability in vitro. The specificity of 64Cu-PSMA-617 was confirmed by cell uptake experiments in PSMA (+) LNCaP cell and PSMA (-) PC-3 and gastric adenocarcinoma BGC-823 cells. Micro-PET imaging in BGC-823 and PC-3 xenografts nude mice was evaluated (n = 4). And the tumors were visualized and better tumor-to-background achieved till 24 h. Co-administration of N- [[[(1S)-1-Carboxy-3-methylbutyl]amino]-carbonyl]-L-glutamic acid (ZJ-43) can substantially block the uptake in those tumors. Dissected tumor tissues were analyzed by auto-radiography and immunohistochemistry, and these results confirmed the PSMA expression in neo-vasculature which explained the target molecular imaging of 64Cu-PSMA-617. All those results suggested 64Cu-PSMA-617 may serve as a novel radio-tracer for tumor imaging more than prostate cancer.

Keywords: 64Cu; PET; gastric cancer; neo-vasculature; prostate specific membrane antigen.

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Conflict of interest statement

CONFLICTS OF INTEREST The authors declare no competing financial interests.

Figures

Figure 1
Figure 1. The radio-labeling and decay of 64Cu-PSMA-617
The dotted line box on the lower left gives the decay properties of related nuclide.
Figure 2
Figure 2. In vitro stability test and cell uptake analysis of 64Cu-PSMA-617
(A) In vitro stability test of 64Cu-PSMA-617 in 0.9% saline (blue) and 5% HSA (red). (B) Cell uptake analysis of 64Cu-PSMA-617 tracer in PSMA(+) LNCaP, PSMA(–) PC-3 and BGC-823 cell lines at 5 min, 30 min, 1 h and 2 h. (**P < 0.01) (n = 4).
Figure 3
Figure 3. Micro-PET images of 64Cu-PSMA-617 in BGC-823 and PC-3 xenograft nude mice
(A) Micro-PET images of 64Cu-PSMA-617 in BGC-823 gastric adenocarcinoma cell xenograft nude mice at 0.5 h, 8 h and 24 h after injection. (B) MIP images of 64Cu-PSMA-617 in BGC-823 bearing mouse with or without co-injection of blocker ZJ-43 (25 mg/kg) at 24 h. Red arrows indicate tumor. (C) Micro-PET images of 64Cu-PSMA-617 in PC-3 prostate cancer cell xenograft nude mice at 1 h, 24 h and 36 h after injection. (D) Micro-PET imaging of 64Cu-PSMA-617 co-injected with ZJ-43 (25 mg/kg) as blocker in PC-3 tumor. Red arrows indicate tumor.
Figure 4
Figure 4. Biodistribution of 64Cu-PSMA-617 in tumor-bearing mice and the auto-radiography images of tumor tissues
(A, B) Biodistribution of various organs of 64Cu-PSMA-617 after 24 h injection in BGC-823 and PC-3 bearing mice (n = 4). The error bar was calculated as the standard deviation. (C–F) Auto-radiography of BGC-823 and PC-3 tumor. C and D are the auto-radiography images of tumor sections (25 µm) obtained from BGC-823 tumor 24 h after injection of 64Cu-PSMA-617. E and F are tumor sections (25 µm) obtained from PC-3 tumor 72 h after injection of 64Cu-PSMA-617. The tumors periphery parts showed intense radio-activity (C, E) which decreased clearly in ZJ-43(25 mg/kg) co-injection group (D, F).
Figure 5
Figure 5. Immunohistochemical analysis of PC-3 tumor
CD34 staining in (A, C) demonstrates staining of the tumor-associated vascular endothelium of tumor in the tumor periphery. Overlap of PSMA staining in the tumor vasculature is shown in (B, D). The enlarged images of the squares in A, B (Scale = 4 mm) are shown in C, D (Scale = 100 μm).
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