Neutrophil Elastase-Activatable Prodrugs Based on an Alkoxyamine Platform to Deliver Alkyl Radicals Cytotoxic to Tumor Cells

Current chemotherapies
suffer low specificity and sometimes drug
resistance. Neutrophil elastase activity in cancer is associated with
poor prognosis and metastasis settlement. More generally, tumors harbor
various and persistent protease activities unseen in healthy tissues.
In an attempt to be more specific, we designed prodrugs that are activatable
by neutrophil elastase. Upon activation, these alkoxyamine-based drugs
release cytotoxic alkyl radicals that act randomly to prevent drug
resistance. As a result, U87 glioblastoma cells displayed high level
caspase 3/7 activation during the first hour of exposure in the presence
of human neutrophil elastase and the prodrug in vitro. The apoptosis
process and cell death occurred between 24 and 48 h after exposure
with a half lethal concentration of 150 μM. These prodrugs are
versatile and easy to synthetize and can be adapted to many enzymes.