Synthesis and Evaluation of a Monomethyl Auristatin ERIntegrin _v6 Binding Peptide-Drug Conjugate for Tumor Targeted Drug Delivery

Many anticancer drugs exhibit high systemic off-targettoxicitiescausing severe side effects. Peptide-drug conjugates (PDCs)that target tumor-specific receptors such as integrin & alpha;(v)& beta;(6) are emerging as powerful tools to overcomethese challenges. The development of an integrin & alpha;(v)& beta;(6)-selective PDC was achieved by combining the therapeuticefficacy of the cytotoxic drug monomethyl auristatin E with the selectivityof the & alpha;(v)& beta;(6)-binding peptide (& alpha;(v)& beta;(6)-BP) and with the ability of positron emissiontomography (PET) imaging by copper-64. The [Cu-64]PDC-1 was produced efficiently and in high purity. The PDC exhibitedhigh human serum stability, integrin & alpha;(v)& beta;(6)-selective internalization, cell binding, and cytotoxicity.Integrin & alpha;(v)& beta;(6)-selective tumor accumulationof the [Cu-64]PDC-1 was visualized with PET-imagingand corroborated by biodistribution, and [Cu-64]PDC-1 showed promising in vivo pharmacokinetics. The [Cu-nat]PDC-1 treatment resulted in prolonged survival ofmice bearing & alpha;(v)& beta;(6) (+) tumors (mediansurvival: 77 days, vs & alpha;(v)& beta;(6) (-)tumor group 49 days, and all other control groups 37 days).