A FLIM photosensitizer: Targeting “Affinal” suborganelles to accelerate cancer cell oxidative stress and apoptosis

An amphiphilic small-molecule PS ( CMOOH ) anchoring on the two original and derived suborganelles (ER and LDs) were prepared, producing ROS for causing ERS and lipophagy to accelerate the apoptosis of cancer cells, of which apoptotic mechanism was observed by CLSM/FLIM. • CMOOH discriminatively visualize derivational suborganelles via FILM. • CMOOH generated ROS to cause rapid cell apoptosis via “knock-on” effect. • The ERS and lipophagy mediated apoptosis were precisely revealed for guiding PDT. The sub-organelle targeting group is generally introduced into photosensitizer (PS) to expedite cancer cell apoptosis through oxidized specifically subcellular organelle for photodynamic therapy (PDT). Nevertheless, the exploitation of PS by targeting original and derived organelles, which might utilize a “knock-on” effect to cause rapid apoptosis, is still a huge challenge. Herein, an amphiphilic small-molecule PS, named CMOOH , was constructed by lipophilic coumarin and hydrophilic hydroxyl group, which not only anchored on the two sub-organelles with a derivational relationship (endoplasmic reticulum (ER) and lipid droplets (LDs)) but also could produce reactive oxygen species (ROS) simultaneously to facilitate the apoptosis of cancer cells under the light irradiation. Encouragingly, CMOOH firstly deciphered the apoptotic mechanism mediated by endoplasmic reticulum stress (ERS) and lipophagy by confocal laser scanning microscopy (CLSM) and two-photon fluorescence lifetime imaging microscopy (FLIM), deriving from the applicable amphipathicity, fluorescent lifetime and excellent nonlinear optical property. This tactic provided an innovative platform for treatment and imaging and renewed awareness of heightening the cancer-cell apoptosis via oxidative damage of “affinal” sub-organelles.