Skip to main content

Advertisement

SpringerLink
Log in

Noninvasive imaging of tumor integrin expression using 18F-labeled RGD dimer peptide with PEG4 linkers

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

Abstract

Purpose

Various radiolabeled Arg-Gly-Asp (RGD) peptides have been previously investigated for tumor integrin αvβ3 imaging. To further develop RGD radiotracers with enhanced tumor-targeting efficacy and improved in vivo pharmacokinetics, we designed a new RGD homodimeric peptide with two PEG4 spacers (PEG4 = 15-amino-4,7,10,13-tetraoxapentadecanoic acid) between the two monomeric RGD motifs and one PEG4 linker on the glutamate α-amino group (18F-labeled PEG4-E[PEG4-c(RGDfK)]2, P-PRGD2), as a promising agent for noninvasive imaging of integrin expression in mouse models.

Methods

P-PRGD2 was labeled with 18F via 4-nitrophenyl 2-18F-fluoropropionate (18F-FP) prosthetic group. In vitro and in vivo characteristics of the new dimeric RGD peptide tracer 18F-FP-P-PRGD2 were investigated and compared with those of 18F-FP-P-RGD2 (18F-labeled RGD dimer without two PEG4 spacers between the two RGD motifs). The ability of 18F-FP-P-PRGD2 to image tumor vascular integrin expression was evaluated in a 4T1 murine breast tumor model.

Results

With the insertion of two PEG4 spacers between the two RGD motifs, 18F-FP-P-PRGD2 showed enhanced integrin αvβ3-binding affinity, increased tumor uptake and tumor-to-nontumor background ratios compared with 18F-FP-P-RGD2 in U87MG tumors. MicroPET imaging with 18F-FP-P-PRGD2 revealed high tumor contrast and low background in tumor-bearing nude mice. Biodistribution studies confirmed the in vivo integrin αvβ3-binding specificity of 18F-FP-P-RGD2. 18F-FP-P-PRGD2 can specifically image integrin αvβ3 on the activated endothelial cells of tumor neovasculature.

Conclusion

18F-FP-P-PRGD2 can provide important information on integrin expression on the tumor vasculature. The high integrin binding affinity and specificity, excellent pharmacokinetic properties and metabolic stability make the new RGD dimeric tracer 18F-FP-P-PRGD2 a promising agent for PET imaging of tumor angiogenesis and for monitoring the efficacy of antiangiogenic treatment.

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

Similar content being viewed by others

References

  1. Carmeliet P, Jain RK. Angiogenesis in cancer and other diseases. Nature 2000;407:249–57. doi: 10.1038/35025220.

    Article  PubMed  CAS  Google Scholar 

  2. Folkman J. Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med 1995;1:27–31. doi: 10.1038/nm0195-27.

    Article  PubMed  CAS  Google Scholar 

  3. Folkman J. Role of angiogenesis in tumor growth and metastasis. Semin Oncol 2002;29:15–8.

    PubMed  CAS  Google Scholar 

  4. Cai W, Chen X. Anti-angiogenic cancer therapy based on integrin αvβ3 antagonism. Anticancer Agents Med Chem 2006;6:407–28. doi: 10.2174/187152006778226530.

    Article  PubMed  CAS  Google Scholar 

  5. Knuuti J, Bengel FM. Positron emission tomography and molecular imaging. Heart 2008;94:360–7. doi: 10.1136/hrt.2007.118992.

    Article  PubMed  CAS  Google Scholar 

  6. Hawkins RA, Hoh C, Glaspy J, Choi Y, Dahlbom M, Rege S, et al. The role of positron emission tomography in oncology and other whole-body applications. Semin Nucl Med 1992;22:268–84. doi: 10.1016/S0001-2998(05)80121-7.

    Article  PubMed  CAS  Google Scholar 

  7. Sharma N, Neumann D, Macklis R. The impact of functional imaging on radiation medicine. Radiat Oncol 2008;3:25. doi: 10.1186/1748-717X-3-25.

    Article  PubMed  CAS  Google Scholar 

  8. Schindler TH, Zhang XL, Vincenti G, Mhiri L, Lerch R, Schelbert HR. Role of PET in the evaluation and understanding of coronary physiology. J Nucl Cardiol 2007;14:589–603. doi: 10.1016/j.nuclcard.2007.05.006.

    Article  PubMed  Google Scholar 

  9. Eliceiri BP, Cheresh DA. The role of alphav integrins during angiogenesis: insights into potential mechanisms of action and clinical development. J Clin Invest 1999;103:1227–30. doi: 10.1172/JCI6869.

    Article  PubMed  CAS  Google Scholar 

  10. Friedlander M, Theesfeld CL, Sugita M, Fruttiger M, Thomas MA, Chang S, et al. Involvement of integrins αvβ3 and αvβ5 in ocular neovascular diseases. Proc Natl Acad Sci USA 1996;93:9764–9. doi:10.1073/pnas.93.18.9764.

    Article  PubMed  CAS  Google Scholar 

  11. Brooks PC, Clark RA, Cheresh DA. Requirement of vascular integrin αvβ3 for angiogenesis. Science 1994;264:569–71. doi: 10.1126/science.7512751.

    Article  PubMed  CAS  Google Scholar 

  12. Gladson CL. Expression of integrin αvβ3 in small blood vessels of glioblastoma tumors. J Neuropathol Exp Neurol 1996;55:1143–9. doi: 10.1097/00005072-199611000-00005.

    Article  PubMed  CAS  Google Scholar 

  13. Li ZB, Cai W, Cao Q, Chen K, Wu Z, He L, et al. 64Cu-labeled tetrameric and octameric RGD peptides for small-animal PET of tumor αvβ3 integrin expression. J Nucl Med 2007;48:1162–71. doi: 10.2967/jnumed.107.039859.

    Article  PubMed  CAS  Google Scholar 

  14. Zhang X, Xiong Z, Wu Y, Cai W, Tseng JR, Gambhir SS, et al. Quantitative PET imaging of tumor integrin αvβ3 expression with 18F-FRGD2. J Nucl Med 2006;47:113–21.

    PubMed  CAS  Google Scholar 

  15. Haubner R, Weber WA, Beer AJ, Vabuliene E, Reim D, Sarbia M, et al. Noninvasive visualization of the activated αvβ3 integrin in cancer patients by positron emission tomography and [18F]galacto-RGD. PLoS Med 2005;2:e70. doi: 10.1371/journal.pmed.0020070.

    Article  PubMed  Google Scholar 

  16. Kenny LM, Coombes RC, Oulie I, Contractor KB, Miller M, Spinks TJ, et al. Phase I trial of the positron-emitting Arg-Gly-Asp (RGD) peptide radioligand 18F-AH111585 in breast cancer patients. J Nucl Med 2008;49:879–86. doi: 10.2967/jnumed.107.049452.

    Article  PubMed  Google Scholar 

  17. Wu Y, Zhang X, Xiong Z, Cheng Z, Fisher DR, Liu S, et al. microPET imaging of glioma integrin αvβ3 expression using 64Cu-labeled tetrameric RGD peptide. J Nucl Med 2005;46:1707–18.

    PubMed  CAS  Google Scholar 

  18. Li ZB, Chen K, Chen X. 68Ga-labeled multimeric RGD peptides for microPET imaging of integrin αvβ3 expression. Eur J Nucl Med Mol Imaging 2008;35:1100–8. doi: 10.1007/s00259-007-0692-y.

    Article  PubMed  CAS  Google Scholar 

  19. Wu Y, Cai W, Chen X. Near-infrared fluorescence imaging of tumor integrin αvβ3 expression with Cy7-labeled RGD multimers. Mol Imaging Biol 2006;8:226–36. doi: 10.1007/s11307-006-0041-8.

    Article  PubMed  Google Scholar 

  20. Shi J, Wang L, Kim YS, Zhai S, Liu Z, Chen X, et al. Improving tumor uptake and excretion kinetics of 99mTc-labeled cyclic arginine-glycine-aspartic (RGD) dimers with triglycine linkers. J Med Chem 2008;51:7980–90. doi: 10.1021/jm801134k.

    Article  PubMed  CAS  Google Scholar 

  21. Liu Z, Niu G, Shi J, Liu S, Wang F, Liu S, et al. (68)Ga-labeled cyclic RGD dimers with Gly(3) and PEG (4) linkers: promising agents for tumor integrin alpha (v)beta(3) PET imaging. Eur J Nucl Med Mol Imaging 2009. doi: 10.1007/s00259-008-1045-1

  22. Wang L, Shi J, Kim YS, Zhai S, Jia B, Zhao H, et al. Improving tumor-targeting capability and pharmacokinetics of 99mTc-labeled cyclic RGD dimers with PEG4 linkers. Mol Pharm 2009;6:231–45. doi: 10.1021/mp800150r.

    Article  PubMed  CAS  Google Scholar 

  23. Chen X, Park R, Hou Y, Khankaldyyan V, Gonzales-Gomez I, Tohme M, et al. MicroPET imaging of brain tumor angiogenesis with 18F-labeled PEGylated RGD peptide. Eur J Nucl Med Mol Imaging 2004;31:1081–9. doi: 10.1007/s00259-003-1452-2.

    Article  PubMed  CAS  Google Scholar 

  24. Wu Z, Li ZB, Cai W, He L, Chin FT, Li F, et al. 18F-labeled mini-PEG spacered RGD dimer (18F-FPRGD2): synthesis and microPET imaging of αvβ3 integrin expression. Eur J Nucl Med Mol Imaging 2007;34:1823–31. doi: 10.1007/s00259-007-0427-0.

    Article  PubMed  CAS  Google Scholar 

  25. Haubner R, Kuhnast B, Mang C, Weber WA, Kessler H, Wester HJ, et al. [18F]Galacto-RGD: synthesis, radiolabeling, metabolic stability, and radiation dose estimates. Bioconjug Chem 2004;15:61–9. doi: 10.1021/bc034170n.

    Article  PubMed  CAS  Google Scholar 

  26. Lacroix M. MDA-MB-435 cells are from melanoma, not from breast cancer. Cancer Chemother Pharmacol 2009;63:567. doi: 10.1007/s00280-008-0776-9.

    Article  PubMed  Google Scholar 

  27. Rae JM, Creighton CJ, Meck JM, Haddad BR, Johnson MD. MDA-MB-435 cells are derived from M14 melanoma cells – a loss for breast cancer, but a boon for melanoma research. Breast Cancer Res Treat 2007;104:13–9. doi: 10.1007/s10549-006-9392-8.

    Article  PubMed  Google Scholar 

  28. Chen X, Hou Y, Tohme M, Park R, Khankaldyyan V, Gonzales-Gomez I, et al. Pegylated Arg-Gly-Asp peptide: 64Cu labeling and PET imaging of brain tumor αvβ3-integrin expression. J Nucl Med 2004;45:1776–83.

    PubMed  CAS  Google Scholar 

  29. 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 

  30. 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 αvβ3. Cancer Res 2006;66:9673–81. doi: 10.1158/0008-5472.CAN-06-1480.

    Article  PubMed  CAS  Google Scholar 

  31. Dijkgraaf I, Kruijtzer JA, Liu S, Soede AC, Oyen WJ, Corstens FH, et al. Improved targeting of the αvβ3 integrin by multimerisation of RGD peptides. Eur J Nucl Med Mol Imaging 2007;34:267–73. doi: 10.1007/s00259-006-0180-9.

    Article  PubMed  CAS  Google Scholar 

  32. Janssen ML, Oyen WJ, Dijkgraaf I, Massuger LF, Frielink C, Edwards DS, et al. Tumor targeting with radiolabeled αvβ3 integrin binding peptides in a nude mouse model. Cancer Res 2002;62:6146–51.

    PubMed  CAS  Google Scholar 

  33. Ferrara N. Vascular endothelial growth factor: basic science and clinical progress. Endocr Rev 2004;25:581–611. doi: 10.1210/er.2003-0027.

    Article  PubMed  CAS  Google Scholar 

  34. Liu S. Radiolabeled multimeric cyclic RGD peptides as integrin αvβ3 targeted radiotracers for tumor imaging. Mol Pharm 2006;3:472–87. doi: 10.1021/mp060049x.

    Article  PubMed  CAS  Google Scholar 

  35. Dijkgraaf I, Boerman OC, Oyen WJ, Corstens FH, Gotthardt M. Development and application of peptide-based radiopharmaceuticals. Anticancer Agents Med Chem 2007;7:543–51.

    PubMed  CAS  Google Scholar 

  36. Boturyn D, Coll JL, Garanger E, Favrot MC, Dumy P. Template assembled cyclopeptides as multimeric system for integrin targeting and endocytosis. J Am Chem Soc 2004;126:5730–9. doi: 10.1021/ja049926n.

    Article  PubMed  CAS  Google Scholar 

  37. Mammen M, Choi S, Whitesides GM. Polyvalent Interactions in biological systems: implications for design and use of multivalent ligands and inhibitors. Angew Chem Int Ed Engl 1998;37:2754–94.

    Article  Google Scholar 

  38. Janssen M, Oyen WJ, Massuger LF, Frielink C, Dijkgraaf I, Edwards DS, et al. Comparison of a monomeric and dimeric radiolabeled RGD-peptide for tumor targeting. Cancer Biother Radiopharm 2002;17:641–6. doi: 10.1089/108497802320970244.

    Article  PubMed  CAS  Google Scholar 

  39. Chen X, Tohme M, Park R, Hou Y, Bading JR, Conti PS. Micro-PET imaging of αvβ3-integrin expression with 18F-labeled dimeric RGD peptide. Mol Imaging 2004;3:96–104. doi: 10.1162/1535350041464892.

    Article  PubMed  CAS  Google Scholar 

  40. Wu Z, Li ZB, Chen K, Cai W, He L, Chin FT, et al. microPET of tumor integrin αvβ3 expression using 18F-labeled PEGylated tetrameric RGD peptide (18F-FPRGD4). J Nucl Med 2007;48:1536–44. doi: 10.2967/jnumed.107.040816.

    Article  PubMed  CAS  Google Scholar 

  41. Chen X, Park R, Tohme M, Shahinian AH, Bading JR, Conti PS. MicroPET and autoradiographic imaging of breast cancer αv-integrin expression using 18F- and 64Cu-labeled RGD peptide. Bioconjug Chem 2004;15:41–9. doi: 10.1021/bc0300403.

    Article  PubMed  Google Scholar 

  42. Haubner R. αvβ3-integrin imaging: a new approach to characterise angiogenesis? Eur J Nucl Med Mol Imaging 2006;33(Suppl 1):54–63. doi: 10.1007/s00259-006-0136-0.

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported in part by the National Cancer Institute (R01 120188, R01 CA119053, R21 CA121842, R21 CA102123, P50 CA114747, U54 CA119367 and R24 CA93862 to X.C.; and R01 CA115883 to S.L.), and by the Department of Energy (DE-FG02–08ER64684 to S.L.). We thank Dr. Kai Chen for kind technical support and also thank the cyclotron teams at Stanford University for 18F-F− production. Z. Liu would like to acknowledge the China Scholarship Council (CSC) for partial financial support during his study at Stanford University.

Author information

Authors and Affiliations

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

    Zhaofei Liu, Shuanglong Liu & Xiaoyuan Chen

  2. Medical Isotopes Research Center, Peking University, Beijing, 100091, China

    Zhaofei Liu & Fan Wang

  3. School of Health Sciences, Purdue University, West Lafayette, IN, 47907, USA

    Shuang Liu

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

    Xiaoyuan Chen

Authors
  1. Zhaofei Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shuanglong Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Fan Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Shuang Liu
    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.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary Figures

(DOC 5043 KB)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Liu, Z., Liu, S., Wang, F. et al. Noninvasive imaging of tumor integrin expression using 18F-labeled RGD dimer peptide with PEG4 linkers. Eur J Nucl Med Mol Imaging 36, 1296–1307 (2009). https://doi.org/10.1007/s00259-009-1112-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00259-009-1112-2

Keywords

Search

Navigation