Multivalency Increases the Binding Strength of RGD Peptidomimetic‐Paclitaxel Conjugates to Integrin α(V)β(3)

This work reports the synthesis of three multimeric RGD peptidomimetic‐paclitaxel conjugates featuring a number of α(V)β(3) integrin ligands ranging from 2 to 4. These constructs were assembled by conjugation of the integrin α(V)β(3) ligand cyclo[DKP‐RGD]‐CH(2)NH(2) with paclitaxel via a 2′‐carbamate with a self‐immolative spacer, the lysosomally cleavable Val‐Ala dipeptide linker, a multimeric scaffold, a triazole linkage, and finally a PEG spacer. Two monomeric conjugates were also synthesized as reference compounds. Remarkably, the new multimeric conjugates showed a binding affinity for the purified integrin α(V)β(3) receptor that increased with the number of integrin ligands (reaching a minimum IC(50) value of 1.2 nm for the trimeric), thus demonstrating that multivalency is an effective strategy to strengthen the ligand–target interactions.