beta-Glucuronidase triggers extracellular MMAE release from an integrin-targeted conjugate

A non-internalizing alpha(v)beta(3) integrin ligand was conjugated to the anticancer drug MMAE through a beta-glucuronidase-responsive linker. In the presence of beta-glucuronidase, only the conjugate bearing a PEG(4) spacer inhibited the proliferation of integrinexpressing cancer cells at low nanomolar concentrations, indicating important structural requirements for the efficacy of these therapeutics.