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68Ga-labeled NOTA-RGD-BBN peptide for dual integrin and GRPR-targeted tumor imaging

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Abstract

Purpose

Radiolabeled Arg-Gly-Asp (RGD) and bombesin (BBN) peptide analogs have been extensively investigated for the imaging of tumor integrin αvβ3 and gastrin-releasing peptide receptor (GRPR) expression, respectively. Recently, we designed and synthesized a RGD-BBN heterodimeric peptide from c(RGDyK) and BBN(7–14) through a glutamate linker. The goal of this study was to investigate the dual receptor-targeting property and tumor diagnostic value of RGD-BBN heterodimeric peptide labeled with generator-eluted 68Ga (t1/2 68 min, β+ 89% and EC 11%), 68Ga-NOTA-RGD-BBN.

Methods

RGD-BBN heterodimer was conjugated with 1,4,7-triazacyclononanetriacetic acid (NOTA) and labeled with 68Ga. The dual receptor binding affinity was investigated by a radioligand competition binding assay. The in vitro and in vivo dual receptor targeting of 68Ga-NOTA-RGD-BBN was evaluated and compared with that of 68Ga-NOTA-RGD and 68Ga-NOTA-BBN.

Results

NOTA-RGD-BBN had integrin αvβ3 and GRPR binding affinities comparable to those of the monomeric RGD and BBN, respectively. The dual receptor targeting property of 68Ga-NOTA-RGD-BBN was validated by blocking studies in a PC-3 tumor model. 68Ga-NOTA-RGD-BBN showed higher tumor uptake than 68Ga-NOTA-RGD and 68Ga-NOTA-BBN. 68Ga-NOTA-RGD-BBN can also image tumors with either integrin or GRPR expression.

Conclusion

68Ga-NOTA-RGD-BBN exhibited dual receptor targeting properties both in vitro and in vivo. The favorable characterizations of 68Ga-NOTA-RGD-BBN such as convenient synthesis, high specific activity, and high tumor uptake, warrant its further investigation for clinical cancer imaging.

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Acknowledgments

This work was supported, in part, by the National Cancer Institute (NCI R01 CA119053, R21 CA121842, P50 CA114747 and U54 CA119367). We thank Drs. Shuanglong Liu and Kai Chen for excellent technical support. Z. Liu would like to acknowledge the China Scholarship Council (CSC) for partial financial support during his study at Stanford University.

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Authors and Affiliations

  1. 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

    Zhaofei Liu, Gang Niu & Xiaoyuan Chen

  2. Medical Isotopes Research Center, Peking University, Beijing, 100191, China

    Zhaofei Liu & Fan Wang

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  1. Zhaofei Liu
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  2. Gang Niu
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  3. Fan Wang
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  4. Xiaoyuan Chen
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Correspondence to Xiaoyuan Chen.

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Suppl. Fig. 1

Immunofluorescent staining of gastrin releasing peptide receptor (GRPR), human integrin αvβv, and murine integrin β3 for normal organs of nude mice (DOC 25189 kb)

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Liu, Z., Niu, G., Wang, F. et al. 68Ga-labeled NOTA-RGD-BBN peptide for dual integrin and GRPR-targeted tumor imaging. Eur J Nucl Med Mol Imaging 36, 1483–1494 (2009). https://doi.org/10.1007/s00259-009-1123-z

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  • DOI: https://doi.org/10.1007/s00259-009-1123-z

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