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Targeting VPAC1 Receptors for Imaging Glioblastoma

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Abstract

Purpose

Scintigraphic imaging of malignant glioblastoma (MG) continues to be challenging. We hypothesized that VPAC1 cell surface receptors can be targeted for positron emission tomography (PET) imaging of orthotopically implanted MG in a mouse model, using a VPAC1-specific peptide [64Cu]TP3805.

Procedures

The expression of VPAC1 in mouse GL261 and human U87 glioma cell lines was determined by western blot. The ability of [64Cu]TP3805 to bind to GL261 and U87 cells was studied by cell-binding. Receptor-blocking studies were performed to validate receptor specificity. GL261 tumors were implanted orthotopically in syngeneic T-bet knockout C57BL/6 mouse brain (N = 15) and allowed to grow for 2–3 weeks. Mice were injected i.v., first with ~ 150 μCi of 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) then 24 h later with ~ 200 μCi of [64Cu]TP3805. In another set of tumor-bearing mice, (N = 5), ionic [64Cu]Cl2 was injected as a control. Mice were imaged at a 2-h post-injection using an Inveon micro-PET/CT, sacrificed and % ID/g of [64Cu]TP3805 and [64Cu]Cl2 were calculated in a tumor, normal brain, and other tissues. For histologic tissue examination, 3-μm thick sections of the tumors and normal brain were prepared, digital autoradiography (DAR) was performed, and then the sections were H&E stained for histologic examination.

Results

Western blots showed a strong signal for VPAC1 on both cell lines. [64Cu]TP3805 cell-binding was 87 ± 1.5 %. Receptor-blocking reduced cell-binding to 24.3 ± 1.5 % (P < 0.01). PET imaging revealed remarkable accumulation of [64Cu]TP3805 in GL261 MG with a negligible background in the normal brain, as compared to [18F]FDG. Micro-PET/CT image analyses and tissue distribution showed that the brain tumor uptake for [64Cu]TP3805 was 8.2 ± 1.7 % ID/g and for [64Cu]Cl2 2.1 ± 0.5 % ID/g as compared to 1.0 ± 0.3 % ID/g and 1.4 ± 0.3 % ID/g for normal mouse brains, respectively. The high tumor/normal brain ratio for [64Cu]TP3805 (8.1 ± 1.1) allowed tumors to be visualized unequivocally. Histology and [64Cu]TP3805 DAR differentiated malignant tumors from healthy brain and confirmed PET findings.

Conclusion

Targeting VPAC1 receptors using [64Cu]TP3805 for PET imaging of MG is a promising novel approach and calls for further investigation.

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Acknowledgments

Technical support by Paul A. Jicman and Kim Lee are gratefully acknowledged.

Funding

The research, in part, was supported by NIH/NCI RO1CA157372 (MLT), NIH/NCI 1S10OD012406 (MLT), and NIH/NCI S10RR23709 (MLT).

Author information

Authors and Affiliations

  1. Department of Radiology, Thomas Jefferson University, Philadelphia, PA, USA

    Sushil K. Tripathi & Mathew L. Thakur

  2. Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA

    Rhonda Kean, Emily Bongiorno & Douglas C. Hooper

  3. Bound Therapeutics LLC, Philadelphia, PA, USA

    Yuan-Yuan Jin

  4. Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA, USA

    Eric Wickstrom

  5. Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA

    Eric Wickstrom & Mathew L. Thakur

  6. Department of Pathology, Thomas Jefferson University, Philadelphia, PA, USA

    Peter A. McCue

  7. Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, PA, USA

    Mathew L. Thakur

  8. Department of Urology, Thomas Jefferson University, Philadelphia, PA, USA

    Mathew L. Thakur

  9. Department of Radiology, Laboratories of Radiopharmaceutical Research and Molecular Imaging, 1020 Locust Street, 359-JAH, Philadelphia, PA, 19107, USA

    Mathew L. Thakur

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  1. Sushil K. Tripathi
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Correspondence to Mathew L. Thakur.

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Conflict of Interest

MLT holds a granted patent on [64Cu]TP3805. Through TJU, the patent is licensed to NuView Pharmaceuticals. Other authors have no conflict of interest.

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Tripathi, S.K., Kean, R., Bongiorno, E. et al. Targeting VPAC1 Receptors for Imaging Glioblastoma. Mol Imaging Biol 22, 293–302 (2020). https://doi.org/10.1007/s11307-019-01388-5

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