Multimeric Presentation of RGD Peptidomimetics Enhances Integrin Binding and Tumor Cell Uptake

The use of multimeric ligands is considered as a promising strategy to improve tumor targeting for diagnosis and therapy. Herein, tetrameric RGD peptidomimetics were designed to target αvβ3 integrin-expressing tumor cells. These compounds were prepared via an oxime chemoselective assembly of cyclo(DKPRGD) ligands and a cyclodecapeptide scaffold that allows a tetrameric presentation. The resulting tetrameric RGD peptidomimetics were shown to improve αvβ3 integrin binding compared to the monomeric form. Interestingly, these compounds were also able to enhance tumor cell endocytosis in the same way as tetrameric RGD peptides. Altogether, the results show the potential of the tetrameric cyclo(DKP-RGD) ligands for in vivo imaging and drug delivery.