De Novo Construction of Glutathione Activatable Photosensitizers Boosts Sequential Photoacoustic and Fluorescence Imaging and Precise Photodynamic Therapy

Activatable photosensitizers (aPSs) have been found to ameliorate controllability of photodynamic therapy (PDT). The nucleophilic aromatic substitution reaction (S_NAr) chemistry, led by 2,4-dinitrobenzenesulfonate group, realizes the switching of aPSs from off to on through the photo-induced electron transfer (PeT) effect. However, the ultra-sensitive reactivity to glutathione (GSH) greatly reduces the precision of diagnosis and PDT. Herein, we focused on the quenching efficiency and precise activation through structure-activity relationships to optimize the phthalocyanine-based aPSs (PcGx). The improved PcGx could distinguish GSH levels from cancer cells to normal cells. Moreover, cancer cell membrane targeting hyaluronic acid carrier is introduced to construct J aggregation-driven nanoplatform (PcGx@HP). This nanoplatform could not only stabilize and enhance the J aggregation, but also obtain the sequential photoacoustic and fluorescence imaging in vivo. Subsequent studies verifies that PcGx@HP could inhibit tumor growth without off-target toxicity in breast cancer xenograft model. This study provides a reliable method for the de novo construction and development of precise aPSs for sequential imaging and photodynamic therapy.