Dual-targeted activatable photosensitizers with aggregation-induced emission (AIE) characteristics for image-guided photodynamic cancer cell ablation

The currently available photosensitizers (PSs) for photodynamic therapy (PDT) can easily lead to undesirable normal cell death due to their intrinsic photo-toxicity and lack of selectivity for cancer cells. Activatable PSs with high therapeutic efficiency towards cancer cells but minimized side effects on normal cells are thus highly desirable. In this work, we developed a probe with dual-targeted activatable PSs that can recognize and ablate cancer cells with high selectivity. The probe is composed of a fluorophore with aggregation-induced emission (AIE) characteristics which can be used as an imaging agent as well as a PS, a quencher moiety that can be cleaved upon encountering biothiols, and a cyclic arginine-glycine-aspartic acid (cRGD) tripeptide for targeting cancer cells with overexpressed α_vβ₃ integrin. The probe itself is non-fluorescent and its ability to generate reactive oxygen species (ROS) is prohibited. However, it could be selectively activated to offer specific fluorescence turn-on with efficient ROS generation in the aggregated state, which was used to ablate cancer cells overexpressing both α_vβ₃ integrin receptors and glutathione. As compared to conventional activatable PSs which show quenched fluorescence and reduced ROS generation in the aggregated state, the dual-selection process with enhanced fluorescence and efficient ROS generation of the activated AIE probe in aggregated state offers a high signal-to-background ratio for MDA-MB-231 cancer cell imaging and ablation. This strategy thus opens up new opportunities for designing activatable PSs with high selectivity and low intrinsic photo-toxicity for photodynamic cancer cell ablation.