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 |
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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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