Improved targeting of the αvβ3 integrin by multimerisation of RGD peptides

Dijkgraaf, I., Kruijtzer, J.A.W., Liu, S., Soede, A.C., Oyen, W.J.G., Corstens, F.H.M., Liskamp, R.M.J. and Boerman, O.C. (2007) Improved targeting of the αvβ3 integrin by multimerisation of RGD peptides. European Journal of Nuclear Medicine and Molecular Imaging, 34(2), pp. 267-273. (doi: 10.1007/s00259-006-0180-9)

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Publisher's URL: http://dx.doi.org/10.1007/s00259-006-0180-9

Abstract

Purpose: The integrin α<sub>v</sub>β<sub>3</sub> is expressed on sprouting endothelial cells and on various tumour cell types. Due to the restricted expression of α<sub>v</sub>β<sub>3</sub> in tumours, α<sub>v</sub>β<sub>3</sub> is considered a suitable receptor for tumour targeting. In this study the α<sub>v</sub>β<sub>3</sub> binding characteristics of an <sup>111</sup>In-labelled monomeric, dimeric and tetrameric RGD analogue were compared. Methods: A monomeric (E-c(RGDfK)), dimeric (E-[c(RGDfK)]<sub>2</sub>), and tetrameric (E{E[c(RGDfK)]<sub>2</sub>}<sub>2</sub>) RGD peptide were synthesised, conjugated with DOTA and radiolabelled with <sup>111</sup>In. In vitro α<sub>v</sub>β<sub>3</sub> binding characteristics were determined in a competitive binding assay. In vivo α<sub>v</sub>β<sub>3</sub> targeting characteristics of the compounds were assessed in mice with SK-RC-52 xenografts. Results: The IC<sub>50</sub> values for DOTA-E-c(RGDfK), DOTA-E-[c(RGDfK)]<sub>2</sub>, and DOTA-E{E[c(RGDfK)]<sub>2</sub>}<sub>2</sub>were 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 α<sub>v</sub>β<sub>3</sub> 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 α<sub>v</sub>β<sub>3</sub>.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Liskamp, Professor Robert
Authors: Dijkgraaf, I., Kruijtzer, J.A.W., Liu, S., Soede, A.C., Oyen, W.J.G., Corstens, F.H.M., Liskamp, R.M.J., and Boerman, O.C.
College/School:College of Science and Engineering > School of Chemistry
Journal Name:European Journal of Nuclear Medicine and Molecular Imaging
ISSN:1619-7070
ISSN (Online):1619-7089

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