A diselenide/disulfide unit was introduced
into camptothecin (CPT),
and two selenoprodrugs (e.g., CPT–Se3 and CPT–Se4) were
identified to show improved potency in killing cancer cells and inhibiting
tumor growth in vivo. Interestingly, the intrinsic
fluorescence of CPT was severely quenched by the diselenide bond.
Both the selenoprodrugs were activated by glutathione with a nearly
complete recovery of CPT’s fluorescence. The activation of
prodrugs was accompanied by the production of selenol intermediates,
which catalyzed the constant conversion of glutathione and oxygen
to oxidized glutathione and superoxides. The diselenide unit is widely
employed in constructing thiol-responsive materials. However, the
selenol intermediates were largely ignored in the activation process
prior to this study. Our work verified that integration of the diselenide
unit may further enhance the parent drug’s efficacy. Also,
the discovery of the fluorescence quenching property of the diselenide/disulfide
bond further shed light on constructing novel theranostic agents.