Tumor microenvironment-activated multi-functional nanodrug with size-enlargement for enhanced cancer phototheranostics

Phototheranostics that integrate diagnosis and treatment modalities have shown great promise in personalized cancer therapy. However, the "always on " characteristics often lead to suboptimal imaging quality and severe side effects. Herein, we report the construction of a perylenemonoimide based nanodrug CPMI NP with multi-functional activatable theranostic capability. The nanodrug is facilely co-assembled from a prodrug CPMI and DSPE-mPEG2000. In a tumor microenvironment (TME) with excessive glutathione (GSH), CPMI undergoes a cascade reaction to generate the phototheranostic molecule NPMI and the chemodrug chlorambucil, simultaneously switching on the near-infrared (NIR) fluorescence, photothermal effect, and drug release. The photothermal conversion efficiency is as high as 52.2%. Moreover, NPMI exhibits an enhanced intermolecular pi-pi stacking effect, leading to significant size-enlargement of the nanodrug and prolonged tumor retention. Due to TME-activation, the strong in vivo fluorescence signal of the tumor can be observed 144 h post injection with a high signal-to-noise ratio of up to 17. The enhanced tumor inhibition efficiency of the nanodrug is confirmed through activatable chemo-photothermal therapy. This work paves the way for the design of activatable phototheranostic agents for accurate cancer diagnosis and treatment.