Synthesis and Evaluation of a Monomethyl Auristatin E─Integrin α<sub>v</sub>β<sub>6</sub> Binding Peptide–Drug Conjugate for Tumor Targeted Drug Delivery
Ryan A. Davis, Tanushree Ganguly, Rebecca Harris, Sven H. Hausner, Luciana Kovacs, Julie L. Sutcliffe
Abstract
High Resolution Image Download MS PowerPoint Slide 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).