Skip to main content

Advertisement

SpringerLink
Log in

Dual-modality optical and positron emission tomography imaging of vascular endothelial growth factor receptor on tumor vasculature using quantum dots

  • Original Article
  • Published:
European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

Abstract

Purpose

To date, the in vivo imaging of quantum dots (QDs) has been mostly qualitative or semiquantitative. The development of a dual-function positron emission tomography (PET)/near-infrared fluorescence (NIRF) probe might allow the accurate assessment of the tumor-targeting efficacy of QDs.

Materials and methods

An amine-functionalized QD was conjugated with VEGF protein and DOTA chelator for VEGFR-targeted PET/NIRF imaging after 64Cu-labeling. The targeting efficacy of this dual functional probe was evaluated in vitro and in vivo through cell-binding assay, cell staining, in vivo optical/PET imaging, ex vivo optical/PET imaging, and histology.

Results

The DOTA–QD–VEGF exhibited VEGFR-specific binding in both cell-binding assay and cell staining experiment. Both NIR fluorescence imaging and microPET showed VEGFR-specific delivery of conjugated DOTA–QD–VEGF nanoparticle and prominent reticuloendothelial system uptake. The U87MG tumor uptake of 64Cu-labeled DOTA–QD was less than one percentage injected dose per gram (%ID/g), significantly lower than that of 64Cu-labeled DOTA–QD–VEGF (1.52 ± 0.6%ID/g, 2.81 ± 0.3%ID/g, 3.84 ± 0.4%ID/g, and 4.16 ± 0.5%ID/g at 1, 4, 16, and 24 h post injection, respectively; n = 3). Good correlation was also observed between the results measured by ex vivo PET and NIRF organ imaging. Histologic examination revealed that DOTA–QD–VEGF primarily targets the tumor vasculature through a VEGF–VEGFR interaction.

Conclusion

We have successfully developed a QD-based nanoprobe for dual PET and NIRF imaging of tumor VEGFR expression. The success of this bifunctional imaging approach may render higher degree of accuracy for the quantitative targeted NIRF imaging in deep tissue.

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
Fig. 8
Fig. 9

Similar content being viewed by others

References

  1. Michalet X, Pinaud FF, Bentolila LA, Tsay JM, Doose S, Li JJ, et al. Quantum dots for live cells, in vivo imaging, and diagnostics. Science 2005;307:538–44.

    Article  PubMed  CAS  Google Scholar 

  2. Cai W, Hsu AR, Li ZB, Chen X. Are quantum dots ready for in vivo imaging in human subjects? Nanoscale Research Letters 2007;2:265–81.

    Article  CAS  Google Scholar 

  3. Bruchez M Jr, Moronne M, Gin P, Weiss S, Alivisatos AP. Semiconductor nanocrystals as fluorescent biological labels. Science 1998;281:2013–6.

    Article  PubMed  CAS  Google Scholar 

  4. Chan WC, Nie S. Quantum dot bioconjugates for ultrasensitive nonisotopic detection. Science 1998;281:2016–8.

    Article  PubMed  CAS  Google Scholar 

  5. Kaul Z, Yaguchi T, Kaul SC, Hirano T, Wadhwa R, Taira K. Mortalin imaging in normal and cancer cells with quantum dot immuno-conjugates. Cell Res 2003;13:503–7.

    Article  PubMed  Google Scholar 

  6. Ness JM, Akhtar RS, Latham CB, Roth KA. Combined tyramide signal amplification and quantum dots for sensitive and photostable immunofluorescence detection. J Histochem Cytochem 2003;51:981–7.

    PubMed  CAS  Google Scholar 

  7. Dahan M, Levi S, Luccardini C, Rostaing P, Riveau B, Triller A. Diffusion dynamics of glycine receptors revealed by single-quantum dot tracking. Science 2003;302:442–5.

    Article  PubMed  CAS  Google Scholar 

  8. Mattheakis LC, Dias JM, Choi YJ, Gong J, Bruchez MP, Liu J, et al. Optical coding of mammalian cells using semiconductor quantum dots. Anal Biochem 2004;327:200–8.

    Article  PubMed  CAS  Google Scholar 

  9. Pathak S, Choi SK, Arnheim N, Thompson ME. Hydroxylated quantum dots as luminescent probes for in situ hybridization. J Am Chem Soc 2001;123:4103–4.

    Article  PubMed  CAS  Google Scholar 

  10. Algar WR, Krull UJ. Towards multi-colour strategies for the detection of oligonucleotide hybridization using quantum dots as energy donors in fluorescence resonance energy transfer (FRET). Anal Chim Acta 2007;581:193–201.

    Article  PubMed  CAS  Google Scholar 

  11. Akerman ME, Chan WC, Laakkonen P, Bhatia SN, Ruoslahti E. Nanocrystal targeting in vivo. Proc Natl Acad Sci USA 2002;99:12617–21.

    Article  PubMed  CAS  Google Scholar 

  12. Cai W, Shin DW, Chen K, Gheysens O, Cao Q, Wang SX, et al. Peptide-labeled near-infrared quantum dots for imaging tumor vasculature in living subjects. Nano Lett 2006;6:669–76.

    Article  PubMed  CAS  Google Scholar 

  13. Gao X, Cui Y, Levenson RM, Chung LWK, Nie S. In vivo cancer targeting and imaging with semiconductor quantum dots. Nat Biotechnol 2004;22:969–76.

    Article  PubMed  CAS  Google Scholar 

  14. Tada H, Higuchi H, Wanatabe TM, Ohuchi N. In vivo real-time tracking of single quantum dots conjugated with monoclonal anti-HER2 antibody in tumors of mice. Cancer Res 2007;67:1138–44.

    Article  PubMed  CAS  Google Scholar 

  15. Cai W, Chen K, Li ZB, Gambhir SS, Chen X. Dual-function probe for PET and near-infrared fluorescence imaging of tumor vasculature. J Nucl Med 2007;48:1862–70.

    Article  PubMed  CAS  Google Scholar 

  16. Li ZB, Cai W, Chen X. Semiconductor quantum dots for in vivo imaging. J Nanosci Nanotechnol 2007;7:2567–81.

    Article  PubMed  CAS  Google Scholar 

  17. Cai W, Chen X. Nanoplatforms for targeted molecular imaging in living subjects. Small 2007;3:1840–54.

    Article  PubMed  CAS  Google Scholar 

  18. Gambhir SS. Molecular imaging of cancer with positron emission tomography. Nat Rev Cancer 2002;2:683–93.

    Article  PubMed  CAS  Google Scholar 

  19. Wang H, Cai W, Chen K, Li ZB, Kashefi A, He L, et al. A new PET tracer specific for vascular endothelial growth factor receptor 2. Eur J Nucl Med Mol Imaging 2007;27:2001–10.

    Article  Google Scholar 

  20. Cai W, Chen K, Mohamedali KA, Cao Q, Gambhir SS, Rosenblum MG, et al. PET of vascular endothelial growth factor receptor expression. J Nucl Med 2006;47:2048–56.

    PubMed  CAS  Google Scholar 

  21. Kim KJ, Li B, Winer J, Armanini M, Gillett N, Phillips HS, et al. Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo. Nature 1993;362:841–4.

    Article  PubMed  CAS  Google Scholar 

  22. Ferrara N, Hillan KJ, Novotny W. Bevacizumab (Avastin), a humanized anti-VEGF monoclonal antibody for cancer therapy. Biochem Biophys Res Commun 2005;333:328–35.

    Article  PubMed  CAS  Google Scholar 

  23. Cai W, Chen X. Multimodality molecular imaging of tumor angiogenesis. J Nucl Med 2008;49:113S–128S.

    Article  PubMed  CAS  Google Scholar 

  24. Cai W, Chen X. Multimodality imaging of vascular endothelial growth factor and vascular endothelial growth factor receptor expression. Front Biosci 2007;12:4267–79.

    Article  PubMed  CAS  Google Scholar 

  25. Wu Y, Zhang X, Xiong Z, Cheng Z, Fisher DR, Liu S, et al. microPET imaging of glioma integrin avb3 expression using 64Cu-labeled tetrameric RGD peptide. J Nucl Med 2005;46:1707–18.

    PubMed  CAS  Google Scholar 

  26. Cai W, Wu Y, Chen K, Cao Q, Tice DA, Chen X. In vitro and in vivo characterization of 64Cu-labeled Abegrin, a humanized monoclonal antibody against integrin avb3. Cancer Res 2006;66:9673–81.

    Article  PubMed  CAS  Google Scholar 

  27. Cai W, Olafsen T, Zhang X, Cao Q, Gambhir SS, Williams LE, et al. PET imaging of colorectal cancer in xenograft-bearing mice by use of an 18F-labeled T84.66 anti-carcinoembryonic antigen diabody. J Nucl Med 2007;48:304–10.

    Article  PubMed  CAS  Google Scholar 

  28. Cai W, Chen X. Preparation of peptide conjugated quantum dots for tumour vasculature targeted imaging. Nat Protoc 2008;3:89–96.

    Article  PubMed  CAS  Google Scholar 

  29. Senior JH. Fate and behavior of liposomes in vivo: a review of controlling factors. Crit Rev Ther Drug Carr Syst 1987;3:123–93.

    CAS  Google Scholar 

  30. Husztik E, Lazar G, Parducz A. Electron microscopic study of Kupffer-cell phagocytosis blockade induced by gadolinium chloride. Br J Exp Pathol 1980;61:624–30.

    PubMed  CAS  Google Scholar 

  31. Diluzio NR, Wooles WR. Depression of phagocytic activity and immune response by methyl palmitate. Am J Physiol 1964;206:939–43.

    PubMed  CAS  Google Scholar 

  32. Storm G, Belliot SO, Daemen T, Lasic DD. Surface modification of nanoparticles to oppose uptake by the mononuclear phagocyte system. Adv Drug Deliv Rev 1995;17:31–48.

    Article  CAS  Google Scholar 

  33. Stolnik S, Illum L, Davis SS. Long circulating microparticulate drug carriers. Adv Drug Deliv Rev 1995;16:195–214.

    Article  CAS  Google Scholar 

  34. Vladimir P, Torchilin VST. Which polymers can make nanoparticulate drug carriers long-circulating? Adv Drug Deliv Rev 1995;16:141–55.

    Article  Google Scholar 

  35. Ferrara N. VEGF and the quest for tumour angiogenesis factors. Nat Rev Cancer 2002;2:795–803.

    Article  PubMed  CAS  Google Scholar 

  36. Ferrara N. Vascular endothelial growth factor: basic science and clinical progress. Endocr Rev 2004;25:581–611.

    Article  PubMed  CAS  Google Scholar 

  37. Soo Choi H, Liu W, Misra P, Tanaka E, Zimmer JP, Itty Ipe B, et al. Renal clearance of quantum dots. Nat Biotechnol 2007;25:1165–70.

    Article  Google Scholar 

  38. Ballou B, Ernst LA, Andreko S, Harper T, Fitzpatrick JA, Waggoner AS, et al. Sentinel lymph node imaging using quantum dots in mouse tumor models. Bioconjug Chem 2007;18:389–96.

    Article  PubMed  CAS  Google Scholar 

  39. Larson DR, Zipfel WR, Williams RM, Clark SW, Bruchez MP, Wise FW, et al. Water-soluble quantum dots for multiphoton fluorescence imaging in vivo. Science 2003;300:1434–6.

    Article  PubMed  CAS  Google Scholar 

  40. Pradhan N, Battaglia DM, Liu Y, Peng X. Efficient, stable, small, and water-soluble doped ZnSe nanocrystal emitters as non-cadmium biomedical labels. Nano Lett 2007;7:312–7.

    Article  PubMed  CAS  Google Scholar 

  41. Massoud TF, Gambhir SS. Molecular imaging in living subjects: seeing fundamental biological processes in a new light. Genes Dev 2003;17:545–80.

    Article  PubMed  CAS  Google Scholar 

  42. Weissleder R, Mahmood U. Molecular imaging. Radiology 2001;219:316–33.

    PubMed  CAS  Google Scholar 

  43. Bass LA, Wang M, Welch MJ, Anderson CJ. In vivo transchelation of copper-64 from TETA-octreotide to superoxide dismutase in rat liver. Bioconjug Chem 2000;11:527–32.

    Article  PubMed  CAS  Google Scholar 

  44. Liu Z, Cai W, He L, Nakayama N, Chen K, Sun X, et al. In vivo biodistribution and highly efficient tumour targeting of carbon nanotubes in mice. Nature Nanotechnology 2007;2:47–52.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by the National Cancer Institute (NCI; R01 CA119053, R21 CA121842, R21 CA102123, P50 CA114747, U54 CA119367, and R24 CA93862), Department of Defense (DOD; W81XWH-07-1-0374, W81XWH-04-1-0697, W81XWH-06-1-0665, W81XWH-06-1-0042, and DAMD17-03-1-0143), and a Benedict Cassen Postdoctoral Fellowship from the Education and Research Foundation of the Society of Nuclear Medicine (to Zi-bo Li and Weibo Cai). We thank Dr. Philip E. Thorpe and Dr. Sophia Ran at UT Southwestern Medical Center, Dallas, for providing the antimouse VEGFR-2 primary antibody. We also thank Dr. Gang Niu for his excellent technical support and the cyclotron team at the University of Wisconsin-Madison for 64Cu production.

Author information

Authors and Affiliations

  1. The Molecular Imaging Program at Stanford (MIPS), Department of Radiology and Bio-X Program, School of Medicine, Stanford University, 1201 Welch Road, P095, Stanford, CA, 94305-5484, USA

    Kai Chen, Zi-Bo Li, Hui Wang, Weibo Cai & Xiaoyuan Chen

Authors
  1. Kai Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zi-Bo Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hui Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Weibo Cai
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xiaoyuan Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Xiaoyuan Chen.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Chen, K., Li, ZB., Wang, H. et al. Dual-modality optical and positron emission tomography imaging of vascular endothelial growth factor receptor on tumor vasculature using quantum dots. Eur J Nucl Med Mol Imaging 35, 2235–2244 (2008). https://doi.org/10.1007/s00259-008-0860-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00259-008-0860-8

Keywords

Search

Navigation