Synthesis and Evaluation of a Monomethyl Auristatin E─Integrin α_vβ₆ Binding Peptide–Drug Conjugate for Tumor Targeted Drug Delivery

Many anticancer drugs exhibit high systemic off-target toxicities causing severe side effects. Peptide-drug conjugates (PDCs) that target tumor-specific receptors such as integrin αvβ6 are emerging as powerful tools to overcome these challenges. The development of an integrin αvβ6-selective PDC was achieved by combining the therapeutic efficacy of the cytotoxic drug monomethyl auristatin E with the selectivity of the αvβ6-binding peptide (αvβ6-BP) and with the ability of positron emission tomography (PET) imaging by copper-64. The [64Cu]PDC-1 was produced efficiently and in high purity. The PDC exhibited high human serum stability, integrin αvβ6-selective internalization, cell binding, and cytotoxicity. Integrin αvβ6-selective tumor accumulation of the [64Cu]PDC-1 was visualized with PET-imaging and corroborated by biodistribution, and [64Cu]PDC-1 showed promising in vivo pharmacokinetics. The [natCu]PDC-1 treatment resulted in prolonged survival of mice bearing αvβ6 (+) tumors (median survival: 77 days, vs αvβ6 (-) tumor group 49 days, and all other control groups 37 days).