Abstract
This work reports the synthesis of three multimeric RGD peptidomimetic‐paclitaxel conjugates featuring a number of αVβ3 integrin ligands ranging from 2 to 4. These constructs were assembled by conjugation of the integrin αVβ3 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 αVβ3 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.
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