Multivalency Increases the Binding Strength of RGD Peptidomimetic-Paclitaxel Conjugates to Integrin ?V?3

This work reports the synthesis of three multimeric RGD peptidomimetic-paclitaxel conjugates featuring a number of ?V?3 integrin ligands ranging from 2 to 4. These constructs were assembled by conjugation of the integrin ?V?3 ligand cyclo[DKP-RGD]-CH2NH2 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 ?V?3 receptor that increased with the number of integrin ligands (reaching a minimum IC50 value of 1.2 nm for the trimeric), thus demonstrating that multivalency is an effective strategy to strengthen the ligand-target interactions.