Synthesis and Evaluation of a Monomethyl Auristatin E—Integrin α(v)β(6) Binding Peptide–Drug Conjugate for Tumor Targeted Drug Delivery

[Image: see text] 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 α(v)β(6) are emerging as powerful tools to overcome these challenges. The development of an integrin α(v)β(6)-selective PDC was achieved by combining the therapeutic efficacy of the cytotoxic drug monomethyl auristatin E with the selectivity of the α(v)β(6)-binding peptide (α(v)β(6)-BP) and with the ability of positron emission tomography (PET) imaging by copper-64. The [(64)Cu]PDC-1 was produced efficiently and in high purity. The PDC exhibited high human serum stability, integrin α(v)β(6)-selective internalization, cell binding, and cytotoxicity. Integrin α(v)β(6)-selective tumor accumulation of the [(64)Cu]PDC-1 was visualized with PET-imaging and corroborated by biodistribution, and [(64)Cu]PDC-1 showed promising in vivo pharmacokinetics. The [(nat)Cu]PDC-1 treatment resulted in prolonged survival of mice bearing α(v)β(6) (+) tumors (median survival: 77 days, vs α(v)β(6) (−) tumor group 49 days, and all other control groups 37 days).