PURPOSE: 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. 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 (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. RESULTS: The IC(50) values for DOTA-E-c(RGDfK), DOTA-E-[c(RGDfK)](2), and DOTA-E{E[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. CONCLUSION: 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).
PURPOSE: 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. 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 (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. RESULTS: The IC(50) values for DOTA-E-c(RGDfK), DOTA-E-[c(RGDfK)](2), and DOTA-E{E[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. CONCLUSION: 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).
Authors: Marcel L Janssen; Wim J Oyen; Ingrid Dijkgraaf; Leon F Massuger; Cathelijne Frielink; D Scott Edwards; Milind Rajopadhye; Henk Boonstra; Frans H Corstens; Otto C Boerman Journal: Cancer Res Date: 2002-11-01 Impact factor: 12.701
Authors: John A F Joosten; Vuokko Loimaranta; Chantal C M Appeldoorn; Sauli Haataja; Fatna Ait El Maate; Rob M J Liskamp; Jukka Finne; Roland J Pieters Journal: J Med Chem Date: 2004-12-16 Impact factor: 7.446
Authors: Ioannis Vrasidas; Sabine André; Paola Valentini; Corina Böck; Martin Lensch; Herbert Kaltner; Rob M Liskamp; Hans-J Gabius; Roland J Pieters Journal: Org Biomol Chem Date: 2003-03-07 Impact factor: 3.876
Authors: Maurício Morais; Paula D Raposinho; Maria Cristina Oliveira; João D G Correia; Isabel Santos Journal: J Biol Inorg Chem Date: 2012-04 Impact factor: 3.358
Authors: Matthew R Dreher; Andrew J Simnick; Karl Fischer; Richard J Smith; Anand Patel; Manfred Schmidt; Ashutosh Chilkoti Journal: J Am Chem Soc Date: 2007-12-18 Impact factor: 15.419