Department of Nuclear Medicine, Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands. I.Dijkgraaf@nucmed.umcn.nl
Feb, 2007
The integrin alpha(v)beta(3) is expressed on sprouting endothelial cells and on various tumour cell types. Due to the restricted expression of alpha(v)beta(3) in tumours, alpha(v)beta(3) is considered a suitable receptor for tumour targeting. In this study the alpha(v)beta(3) binding characteristics of an (111)In-labelled monomeric, dimeric and tetrameric RGD analogue were compared.A monomeric (E-c(RGDfK)), dimeric (E-[c(RGDfK)](2)), and tetrameric (EE[c(RGDfK)](2)(2)) RGD peptide were synthesised, conjugated with DOTA and radiolabelled with (111)In. In vitro alpha(v)beta(3) binding characteristics were determined in a competitive binding assay. In vivo alpha(v)beta(3) targeting characteristics of the compounds were assessed in mice with SK-RC-52 xenografts.The IC(50) values for DOTA-E-c(RGDfK), DOTA-E-[c(RGDfK)](2), and DOTA-EE[c(RGDfK)](2)(2)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.Multimerisation of c(RGDfK) resulted in enhanced affinity for alpha(v)beta(3) 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 alpha(v)beta(3).