Preliminary biological evaluation of 68Ga-labeled cyclic RGD dimer as an integrin αvβ3-targeting radiotracer for tumor PET imaging

  • Hui Ma
  • Shaoyu Liu
  • Zhanwen Zhang
  • Ganghua TangEmail author
  • Gongjun Yuan
  • Jing Zhao
  • Shu Su


Radiolabeled cyclic arginine-glycine-aspartic acid (RGD) peptides have been widely prepared for noninvasive monitoring of tumor angiogenesis. The aim of this study was to explore and evaluate the feasibility of a novel 68Ga-labeled RGD peptide for tumor angiogenesis imaging. [68Ga]Ga-NOTA-PEG3-β-Glu-RGD2, a cyclic RGD dimer with a symmetric β-glutamate linker, was successfully designed and radiolabeled in high radiochemical yields. A series of experiments in vivo and in vitro were investigated to perform a preliminary evaluation and confirm good target at integrin αvβ3-positive tumor cells. The results suggest that [68Ga]Ga-NOTA-PEG3-β-Glu-RGD2 may be a promising radiotracer for positron emission tomography imaging of tumor angiogenesis.


αvβ3 Integrin RGD peptides Angiogenesis Gallium-68 PET imaging 



This study was funded in part by the Science and Technology Foundation of Guangdong Province (No. 2016B090920087), the Science and Technology Planning Project Foundation of Guangzhou (Nos. 201604020169 and 201510010145), the National Natural Science Foundation of China (Nos. 81571704, 81671719 and 81770505), the Natural Science Foundation of Guangdong Province (No. 2015A030313067), the Research Project of Shanghai Municipal Health and Family Planning Commission (No. 201740060), and China Postdoctoral Science Foundation (Nos. 2018M631029 and 2019T120775).

Supplementary material

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Supplementary material 1 (DOCX 4408 kb)


  1. 1.
    Liu S (2009) Radiolabeled cyclic RGD peptides as integrin αvβ3-targeted radiotracers: maximizing binding affinity via bivalency. Bioconjug Chem 20:2199–2213CrossRefGoogle Scholar
  2. 2.
    Decristoforo C, Hernandez Gonzalez I, Carlsen J, Rupprich M, Huisman M, Virgolini I, Wester HJ, Haubner R (2008) 68Ga- and 111In-labelled DOTA-RGD peptides for imaging of αvβ3 integrin expression. Eur J Nucl Med Mol Imaging 35:1507–1515CrossRefGoogle Scholar
  3. 3.
    Risau W (1997) Mechanisms of angiogenesis. Nature 386:671–674CrossRefGoogle Scholar
  4. 4.
    Li ZB, Chen K, Chen X (2008) 68Ga-labeled multimeric RGD peptides for microPET imaging of integrin αvβ3 expression. Eur J Nucl Med Mol Imaging 35:1100–1108CrossRefGoogle Scholar
  5. 5.
    Liu S, Liu Z, Chen K, Yan Y, Watzlowik P, Wester HJ, Chin FT, Chen X (2010) 18F-Labeled galacto and PEGylated RGD dimers for PET imaging of αvβ3 integrin expression. Mol Imaging Biol 12:530–538CrossRefGoogle Scholar
  6. 6.
    Wu Y, Zhang X, Xiong Z, Cheng Z, Fisher DR, Liu S, Gambhir SS, Chen XY (2005) MicroPET imaging of glioma integrin αvβ3 expression using 64Cu-labeled tetrameric RGD peptide. J Nucl Med 46:1707–1718Google Scholar
  7. 7.
    Liu Z, Niu G, Shi J, Liu S, Wang F, Liu S, Chen X (2009) 68Ga-labeled cyclic RGD dimers with Gly3 and PEG4 linkers: promising agents for tumor integrin αvβ3 PET imaging. Eur J Nucl Med Mol Imaging 36:947–957CrossRefGoogle Scholar
  8. 8.
    Hu K, Tang X, Tang G, Yao SB, Yao BG, Wang HL, Nie DH, Liang X, Tang CH, He SZ (2015) 18F-FP-PEG2-beta-Glu-RGD2: a symmetric integrin αvβ3-targeting radiotracer for tumor PET imaging. PLoS ONE 10:e0138675CrossRefGoogle Scholar
  9. 9.
    Decristoforo C, Knopp R, von Guggenberg E, Rupprich M, Dreger T, Hess A, Virgolini I, Haubner R (2007) A fully automated synthesis for the preparation of 68Ga-labelled peptides. Nucl Med Commun 28:870–875CrossRefGoogle Scholar
  10. 10.
    Poschenrieder A, Schottelius M, Schwaiger M, Kessler H, Wester HJ (2016) The influence of different metal-chelate conjugates of pentixafor on the CXCR10 affinity. EJNMMI Res 6(1):36CrossRefGoogle Scholar
  11. 11.
    Poschenrieder A, Schottelius M, Schwaiger M, Wester Hans-Jürgen (2016) Preclinical evaluation of [68Ga]NOTA-pentixafor for PET imaging of CXCR11 expression in vivo: a comparison to [68Ga]pentixafor. EJNMMI Res 6(1):70CrossRefGoogle Scholar
  12. 12.
    Smith PK, Krohn RI, Hermanson GT, Mallia AK, Gartner FH, Provenzano MD, Fujimoto EK, Goeke NM, Olson BJ, Klenk DC (1985) Measurement of protein using bicinchoninic acid. Anal Biochem 150:76–85CrossRefGoogle Scholar
  13. 13.
    Tang GH, Tang XL, Zhang XS (2009) Synthesis of 18F-FA-BBN-3-Glu-RGD as a new targeted dual-receptor hybrid molecular imaging agent. J Nucl Med 50:2Google Scholar
  14. 14.
    Pohle K, Notni J, Bussemer J, Kessler H, Schwaiger M, Beer AJ (2012) 68Ga-NODAGA-RGD is a suitable substitute for 18F-Galacto-RGD and can be produced with high specific activity in a cGMP/GRP compliant automated process. Nucl Med Biol 39(6):777–784CrossRefGoogle Scholar
  15. 15.
    Lobeek D, Franssen GM, Ma MT, Wester HJ, Decristoforo C, Oyen WJ, Boerman OC, Terry SY, Rijpkema M (2018) In vivo characterization of 4 68Ga-labeled multimeric RGD peptides to image αvβ3 integrin expression in 2 human tumor xenograft mouse models. J Nucl Med 59:1296–1301CrossRefGoogle Scholar
  16. 16.
    Wang L, Shi J, Kim YS, Zhai S, Jia B, Zhao H, Liu Z, Wang F, Chen X, Liu S (2009) Improving tumor-targeting capability and pharmacokinetics of 99mTc-labeled cyclic RGD dimers with PEG4 linkers. Mol Pharm 6(1):231–245CrossRefGoogle Scholar
  17. 17.
    Wu Z, Li ZB, Chen K, Cai W, He L, Chin FT, Li F, Chen X (2007) microPET of tumor integrin alphavbeta3 expression using 18F-labeled PEGylated tetrameric RGD peptide (18F-FPRGD4). J Nucl Med 48:1536–1544CrossRefGoogle Scholar
  18. 18.
    Oxboel J, Brandtlarsen M, Schjoetheskesen C, Myschetzky R, Elali HH, Madsen J, Kjaer A (2014) Comparison of two new angiogenesis PET tracers 68Ga-NODAGA-E[c(RGDyK)]2 and 64Cu-NODAGA-E[c(RGDyK)]2; in vivo imaging studies in human xenograft tumors. Nucl Med Biol 41:259–267CrossRefGoogle Scholar
  19. 19.
    Lang L, Li W, Guo N, Ma Y, Zhu L, Kiesewetter DO, Shen BZ, Niu G, Chen XY (2011) Comparison study of [18F]FAl-NOTA-PRGD2, [18F]FPPRGD2, and [68Ga]Ga-NOTA-PRGD2 for PET imaging of U87MG tumors in mice. Bioconjug Chem 22(12):2415–2422CrossRefGoogle Scholar

Copyright information

© Akadémiai Kiadó, Budapest, Hungary 2019

Authors and Affiliations

  1. 1.Department of Nuclear Medicine and Guangdong Engineering Research Center for Translational Application of Medical RadiopharmaceuticalsThe First Affiliated Hospital, Sun Yat-sen UniversityGuangzhouChina
  2. 2.Department of Nuclear MedicineThe Sixth Affiliated Hospital, Sun Yat-sen UniversityGuangzhouChina

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