European Journal of Nuclear Medicine and Molecular Imaging

, Volume 34, Issue 2, pp 267–273

Improved targeting of the αvβ3 integrin by multimerisation of RGD peptides

  • Ingrid Dijkgraaf
  • John A. W. Kruijtzer
  • Shuang Liu
  • Annemieke C. Soede
  • Wim J. G. Oyen
  • Frans H. M. Corstens
  • Rob M. J. Liskamp
  • Otto C. Boerman
Original article

DOI: 10.1007/s00259-006-0180-9

Cite this article as:
Dijkgraaf, I., Kruijtzer, J.A.W., Liu, S. et al. Eur J Nucl Med Mol Imaging (2007) 34: 267. doi:10.1007/s00259-006-0180-9

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.

Keywords

MultimerisationRGD peptidesAlpha-v-beta-3 integrin receptorSK-RC-52 tumourIndium-111

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • Ingrid Dijkgraaf
    • 1
    • 2
  • John A. W. Kruijtzer
    • 2
  • Shuang Liu
    • 3
  • Annemieke C. Soede
    • 1
  • Wim J. G. Oyen
    • 1
  • Frans H. M. Corstens
    • 1
  • Rob M. J. Liskamp
    • 2
  • Otto C. Boerman
    • 1
  1. 1.Department of Nuclear MedicineRadboud University Nijmegen Medical CentreNijmegenThe Netherlands
  2. 2.Department of Medicinal Chemistry, Utrecht Institute for Pharmaceutical SciencesUtrecht UniversityUtrechtThe Netherlands
  3. 3.School of Health SciencesPurdue UniversityWest LafayetteUSA