Multivalency Increases the Binding Strength of RGD Peptidomimetic-Paclitaxel Conjugates to Integrin αVβ3

Herein we report the synthesis of three multimeric RGD peptidomimetic-paclitaxel conjugates featuring a number of αVβ3 integrin ligands ranging from 2 to 4 (compounds 7-9). These constructs were assembled by conjugation of the integrin αVβ3 ligand cyclo[DKP-RGD]-CH2NH2 (2) with paclitaxel (3) 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 (compounds 5-6) were also synthesized as reference compounds. Remarkably, the new multimeric conjugates showed a binding affinity for the purified integrin αVβ3 receptor which 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.