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