Synthesis and Evaluation of a Monomethyl Auristatin E─Integrin αvβ6 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 α_vβ₆ are emerging as powerful tools to overcome these challenges. The development of an integrin α_vβ₆-selective PDC was achieved by combining the therapeutic efficacy of the cytotoxic drug monomethyl auristatin E with the selectivity of the α_vβ₆-binding peptide (α_vβ₆-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 α_vβ₆-selective internalization, cell binding, and cytotoxicity. Integrin α_vβ₆-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 α_vβ₆ (+) tumors (median survival: 77 days, vs α_vβ₆ (-) tumor group 49 days, and all other control groups 37 days).