Synthesis and biological evaluation of potent αvβ3-integrin receptor antagonists

Introductionαvβ3 Integrin is expressed in sprouting endothelial cells in growing tumors, whereas it is absent in quiescent blood vessels. In addition, various tumor cell types express αvβ3 integrin. αvβ3 Integrin, a transmembrane heterodimeric protein, binds to the arginine–glycine–aspartic acid (RGD) amino acid sequence of extracellular matrix proteins such as vitronectin and plays a pivotal role in invasion, proliferation and metastasis. Due to the selective expression of αvβ3 integrin in tumors, radiolabeled RGD peptides and peptidomimetics are attractive candidates for tumor targeting.MethodsA cyclic RGD peptide, a peptoid–peptide hybrid, an all-peptoid and a peptidomimetic compound were synthesized, conjugated with 1,4,7,10-tetraazadodecane-N,N′,N″,N‴-tetraacetic acid (DOTA) and radiolabeled with 111In. Their in vitro and in vivo αvβ3-binding characteristics were determined.ResultsIC50 values were 236 nM for DOTA-E-c(RGDfK), 219 nM for DOTA-peptidomimetic, >10 mM for DOTA-all-peptoid and 9.25 mM for the peptoid–peptide hybrid DOTA-E-c(nRGDfK). 111In-labeled compounds, except for [111In]DOTA-all-peptoid, showed specific uptake in human αvβ3-expressing tumors xenografted in athymic mice. Tumor uptake for [111In]DOTA-E-c(RGDfK) was 1.73±0.4% ID/g (2 h postinjection) and that of [111In]DOTA-peptidomimetic was 2.04±0.3% ID/g. Tumor uptake for the peptoid–peptide hybrid [111In]DOTA-E-c(nRGDfK) was markedly lower (0.45±0.07% ID/g). The all-peptoid [111In]DOTA-E-c(nRGnDnFnK) did not show specific uptake in tumors (0.11±0.04% ID/g).ConclusionsThe peptidomimetic compound and the cyclic RGD peptide have a high affinity for αvβ3 integrin, and these compounds have better tumor-targeting characteristics than the peptoid–peptide hybrid and the all-peptoid.