Skip to main content

Advertisement

SpringerLink
Log in

Dual-Modality Micro-Positron Emission Tomography/Computed Tomography and Near-Infrared Fluorescence Imaging of EphB4 in Orthotopic Glioblastoma Xenograft Models

  • Research Article
  • Published:
Molecular Imaging and Biology Aims and scope Submit manuscript

Abstract

Purpose

In glioblastoma, EphB4 receptors, a member of the largest family of receptor tyrosine kinases, are overexpressed in both tumor cells and angiogenic blood vessels. The purpose of this study was to examine whether the EphB4-binding peptide TNYL-RAW labeled with both 64Cu and near-infrared fluorescence dye Cy5.5 could be used as a molecular imaging agent for dual-modality positron emission tomography/computed tomography [PET/CT] and optical imaging of human glioblastoma in orthotopic brain tumor models.

Materials and Methods

TNYL-RAW was conjugated to Cy5.5 and the radiometal chelator 1,4,7,10-tetraazadodecane-N,N′,N″,N‴-tetraacetic acid. The conjugate was then labeled with 64Cu for in vitro binding and in vivo dual μPET/CT and optical imaging studies in nude mice implanted with EphB4-expressing U251 and EphB4-negative U87 human glioblastoma cells. Tumors and brains were removed at the end of the imaging sessions for immunohistochemical staining and fluorescence microscopic examinations.

Results

μPET/CT and near-infrared optical imaging clearly showed specific uptake of the dual-labeled TNYL-RAW peptide in both U251 and U87 tumors in the brains of the nude mice after intravenous injection of the peptide. In U251 tumors, the Cy5.5-labeled peptide colocalized with both tumor blood vessels and tumor cells; in U87 tumors, the tracer colocalized only with tumor blood vessels, not with tumor cells.

Conclusions

Dual-labeled EphB4-specific peptide could be used as a noninvasive molecular imaging agent for PET/CT and optical imaging of glioblastoma owing to its ability to bind to both EphB4-expressing angiogenic blood vessels and EphB4-expressing tumor cells.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Furnari FB, Fenton T, Bachoo RM et al (2007) Malignant astrocytic glioma: genetics, biology, and paths to treatment. Genes Dev 21(2):683–710

    Google Scholar 

  2. Wen PY, Kesari S (2008) Malignant gliomas in adults. New Engl J Med 359:492–507

    Article  CAS  PubMed  Google Scholar 

  3. Murai KK, Pasquale EB (2003) ‘Eph’ective signaling: forward, reverse and crosstalk. J Cell Sci 116:2823–2832

    Article  CAS  PubMed  Google Scholar 

  4. Flanagan JG, Vanderhaeghen P (1998) The ephrins and Eph receptors in neural development. Annu Rev Neurosci 21:309–345

    Article  CAS  PubMed  Google Scholar 

  5. Boyd AW, Lackmann M (2001) Signals from Eph and ephrin proteins: a developmental tool kit. Sci STKE 2001:re20

    CAS  PubMed  Google Scholar 

  6. Holder N, Klein R (1999) Eph receptors and ephrins: effectors of morphogenesis. Development 126:2033–2044

    CAS  PubMed  Google Scholar 

  7. Cheng N, Brantley DM, Chen J (2002) The ephrins and Eph receptors in angiogenesis. Cytokine Growth Factor Rev 13:75–85

    Article  CAS  PubMed  Google Scholar 

  8. Durbin L, Brennan C, Shiomi K et al (1998) Eph signaling is required for segmentation and differentiation of the somites. Genes Dev 12:3096–3109

    Article  CAS  PubMed  Google Scholar 

  9. Pasquale EB, Deerinck TJ, Singer SJ, Ellisman MH (1992) Cek5, a membrane receptor-type tyrosine kinase, is in neurons of the embryonic and postnatal avian brain. J Neurosci 12:3956–3967

    CAS  PubMed  Google Scholar 

  10. Dodelet VC, Pasquale EB (2000) Eph receptors and ephrin ligands: embryogenesis to tumorigenesis. Oncogene 19:5614–5619

    Article  CAS  PubMed  Google Scholar 

  11. Easty DJ, Herlyn M, Bennett DC (1995) Abnormal protein tyrosine kinase gene expression during melanoma progression and metastasis. Int J Cancer 60:129–136

    Article  CAS  PubMed  Google Scholar 

  12. Kiyokawa E, Takai S, Tanaka M et al (1994) Overexpression of ERK, an EPH family receptor protein tyrosine kinase, in various human tumors. Cancer Res 54:3645–3650

    CAS  PubMed  Google Scholar 

  13. Wicks IP, Wilkinson D, Salvaris E, Boyd AW (1992) Molecular cloning of HEK, the gene encoding a receptor tyrosine kinase expressed by human lymphoid tumor cell lines. Proc Natl Acad Sci U S A 89:1611–1615

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  14. Erber R, Eichelsbacher U, Powajbo V et al (2006) EphB4 controls blood vascular morphogenesis during postnatal angiogenesis. EMBO J 25:628–641

    Article  CAS  PubMed  Google Scholar 

  15. Koolpe M, Burgess R, Dail M, Pasquale EB (2005) EphB receptor-binding peptides identified by phage display enable design of an antagonist with ephrin-like affinity. J Biol Chem 280:17301–17311

    Article  CAS  PubMed  Google Scholar 

  16. Kumar SR, Scehnet JS, Ley EJ et al (2009) Preferential induction of EphB4 over EphB2 and its implication in colorectal cancer progression. Cancer Res 69:3736–3745

    Article  CAS  PubMed  Google Scholar 

  17. Kumar SR, Singh J, Xia G et al (2006) Receptor tyrosine kinase EphB4 is a survival factor in breast cancer. Am J Pathol 169:279–293

    Article  CAS  PubMed  Google Scholar 

  18. Nakamoto M, Bergemann AD (2002) Diverse roles for the Eph family of receptor tyrosine kinases in carcinogenesis. Microsc Res Tech 59:58–67

    Article  CAS  PubMed  Google Scholar 

  19. Pasquale EB (2005) EPH receptor signaling casts a wide net on cell behavior. Nat Rev Mol Cell Bio 6:462–475

    Article  CAS  Google Scholar 

  20. Xia G, Kumar SP, Stein JP et al (2006) EphB4 receptor tyrosine kinase is expressed in bladder cancer and provides signals for cell survival. Oncogene 25:769–780

    Article  CAS  PubMed  Google Scholar 

  21. Xiong CY, Huang MA, Zhang R et al (2011) In vivo small-animal PET/CT of EphB4 receptors using Cu-64-labeled peptide. J Nucl Med 52:241–248

    Article  CAS  PubMed  Google Scholar 

  22. Zhang R, Xiong CY, Huang M et al (2011) Peptide-conjugated polymeric micellar nanoparticles for Dual SPECT and optical imaging of EphB4 receptors in prostate cancer xenografts. Biomaterials 32:5872–5879

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. Wang W, Ke S, Kwon S et al (2007) A new optical and nuclear dual-labeled imaging agent targeting interleukin 11 receptor alpha-chain. Bioconjug Chem 18:397–402

    Article  CAS  PubMed  Google Scholar 

  24. Grinvald A, Frostig RD, Lieke E, Hildesheim R (1988) Optical imaging of neuronal activity. Physiol Rev 68:1285–1366

    CAS  PubMed  Google Scholar 

  25. Gibson AP, Hebden JC, Arridge SR (2005) Recent advances in diffuse optical imaging. Phys Med Biol 50:R1–R43

    Article  CAS  PubMed  Google Scholar 

  26. Bremer C, Ntziachristos V, Weissleder R (2003) Optical-based molecular imaging: contrast agents and potential medical applications. Eur Radiol 13:231–243

    PubMed  Google Scholar 

  27. Hielscher AH (2005) Optical tomographic imaging of small animals. Curr Opin Biotech 16:79–88

    Article  CAS  PubMed  Google Scholar 

  28. Licha K, Olbrich C (2005) Optical imaging in drug discovery and diagnostic applications. Adv Drug Deliv Rev 57:1087–1108

    Article  CAS  PubMed  Google Scholar 

  29. Niell CM, Smith SJ (2004) Live optical imaging of nervous system development. Annu Rev Physiol 66:771–798

    Article  CAS  PubMed  Google Scholar 

  30. Roessler K, Becherer A, Donat M et al (2012) Intraoperative tissue fluorescence using 5-aminolevolinic acid (5-ALA) is more sensitive than contrast MRI or amino acid positron emission tomography (18F-FET PET) in glioblastoma surgery. Neurol Res 34:314–317

    CAS  PubMed  Google Scholar 

  31. Stummer W, Pichlmeier U, Meinel T et al (2006) Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial. Lancet Oncol 7:392–401

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We thank Erica Goodoff for editing the manuscript. This work was supported in part by the John S. Dunn Foundation. The small animal imaging facility of the University of Texas MD Anderson Cancer Center is supported in part by the National Institutes of Health through MD Anderson Cancer Center Support Grant CA016672.

Conflict of Interest

The authors declare that they have no conflicts of interest.

Author information

Authors and Affiliations

  1. Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Unit 59, 1515 Holcombe Boulevard, Houston, TX, 77030, USA

    Miao Huang, Chiyi Xiong, Rui Zhang, Min Zhou, Qian Huang & Chun Li

  2. Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, The University of Rhode Island, Kingston, RI, USA

    Wei Lu

  3. Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, USA

    Jeffrey Weinberg

Authors
  1. Miao Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Chiyi Xiong
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Wei Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Rui Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Min Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Qian Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jeffrey Weinberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Chun Li
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Chun Li.

Additional information

Miao Huang, Chiyi Xiong, and Wei Lu made equal contribution to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Huang, M., Xiong, C., Lu, W. et al. Dual-Modality Micro-Positron Emission Tomography/Computed Tomography and Near-Infrared Fluorescence Imaging of EphB4 in Orthotopic Glioblastoma Xenograft Models. Mol Imaging Biol 16, 74–84 (2014). https://doi.org/10.1007/s11307-013-0674-3

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11307-013-0674-3

Key words

Search

Navigation