A self-immolated fluorogenic agent triggered by HS exhibiting potential anti-glioblastoma activity.

Glioblastoma is the most common and aggressive type of malignant brain tumor with poor survival and limited therapeutic options. Theranostic anticancer agents with dual functions of diagnosis and therapy are highly attractive. Self-immolation reaction is a promising approach for theranostic prodrugs triggered by the tumor microenvironment. Overexpression of hydrogen sulfide (HS) in glioma cells becomes a potential stimulus for activating prodrugs. Herein, a novel HS responsive agent (SNF) containing amonafide (ANF), a self-immolative linker and a trigger group has been developed for imaging and chemotherapy in living cells. SNF exhibited high selectivity and sensitivity towards HS and also showed excellent lysosome-targeted capability. The activated SNF could translocate to the nucleus, causing DNA damage and blocking the cell cycle. More mechanistic studies indicated that SNF altered the mitochondrial membrane potential and induced autophagy in human glioblastoma-astrocytoma (U87MG). In addition, 3D multicellular U87MG tumor spheroids were used to further confirm the active drug release and high anti-proliferative activity of SNF. This approach may provide a general strategy for developing HS-triggered prodrugs for synergic cancer therapy.