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Improved targeting of the αvβ3 integrin by multimerisation of RGD peptides

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European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

Abstract

Purpose

The integrin αvβ3 is expressed on sprouting endothelial cells and on various tumour cell types. Due to the restricted expression of αvβ3 in tumours, αvβ3 is considered a suitable receptor for tumour targeting. In this study the αvβ3 binding characteristics of an 111In-labelled monomeric, dimeric and tetrameric RGD analogue were compared.

Methods

A monomeric (E-c(RGDfK)), dimeric (E-[c(RGDfK)]2), and tetrameric (E{E[c(RGDfK)]2}2) RGD peptide were synthesised, conjugated with DOTA and radiolabelled with 111In. In vitro αvβ3 binding characteristics were determined in a competitive binding assay. In vivo αvβ3 targeting characteristics of the compounds were assessed in mice with SK-RC-52 xenografts.

Results

The IC50 values for DOTA-E-c(RGDfK), DOTA-E-[c(RGDfK)]2, and DOTA-E{E[c(RGDfK)]2}2were 120 nM, 69.9 nM and 19.6 nM, respectively. At all time points, the tumour uptake of the dimer was significantly higher as compared to that of the monomer. At 8 h p.i., tumour uptake of the tetramer (7.40±1.12%ID/g) was significantly higher than that of the monomer (2.30±0.34%ID/g), p<0.001, and the dimer (5.17±1.22%ID/g), p<0.05. At 24 h p.i., the tumour uptake was significantly higher for the tetramer (6.82±1.41%ID/g) than for the dimer (4.22±0.96%ID/g), p<0.01, and the monomer (1.90±0.29%ID/g), p<0.001.

Conclusion

Multimerisation of c(RGDfK) resulted in enhanced affinity for αvβ3 as determined in vitro. Tumour uptake of a tetrameric RGD peptide was significantly higher than that of the monomeric and dimeric analogues, presumably owing to the enhanced statistical likelihood for rebinding to αvβ3.

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Acknowledgements

We thank Gerry Grutters and Hennie Eikholt for technical assistance during animal experiments. All animal experiments were approved by the local animal welfare committee in accordance with the Dutch legislation and carried out in accordance with their guidelines.

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Authors and Affiliations

  1. Department of Nuclear Medicine, Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands

    Ingrid Dijkgraaf, Annemieke C. Soede, Wim J. G. Oyen, Frans H. M. Corstens & Otto C. Boerman

  2. Department of Medicinal Chemistry, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, P.O. Box 80082, 3508 TB, Utrecht, The Netherlands

    Ingrid Dijkgraaf, John A. W. Kruijtzer & Rob M. J. Liskamp

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

    Shuang Liu

Authors
  1. Ingrid Dijkgraaf
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  2. John A. W. Kruijtzer
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  3. Shuang Liu
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  4. Annemieke C. Soede
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  5. Wim J. G. Oyen
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  6. Frans H. M. Corstens
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  7. Rob M. J. Liskamp
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  8. Otto C. Boerman
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Correspondence to Ingrid Dijkgraaf.

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Dijkgraaf, I., Kruijtzer, J.A.W., Liu, S. et al. Improved targeting of the αvβ3 integrin by multimerisation of RGD peptides. Eur J Nucl Med Mol Imaging 34, 267–273 (2007). https://doi.org/10.1007/s00259-006-0180-9

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  • DOI: https://doi.org/10.1007/s00259-006-0180-9

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