Esterase-Activated Theranostic Prodrug for Dual Organelles-Targeted Imaging and Synergetic Chemo-Photodynamic Cancer Therapy

Activatable prodrugs have received considerable attention in cancer therapy due to their high specificity and reduced side effects. However, the theranostic prodrug with multiple cancerous organelles targeting and combinational therapy is still rare. In this report, an esterase-responsive prodrug tetraphenylethylene functionalized quinolinium-ester-chlorambucil (TPEQC) was developed for dual organelles-targeted and image-guided cancer therapy through synergetic chemotherapy (CT) and photodynamic therapy (PDT). TPE-QC was constructed by conjugating an anticancer drug of chlorambucil with an aggregation-induced emission active photosensitizer of tetraphenylethylene functionalized hydroxyethyl quinolinium (TPE-QO) via the hydrolyzable ester linkage. The fluorescence and photosensitization of TPE-QC were initially quenched because of the photoinduced electron transfer (PET) effect. After reacting with esterase, the ester group of TPE-QC could be selectively hydrolyzed to release chlorambucil and TPE-QO, which terminated the PET process and switched on the fluorescence and photosensitization. Benefitting from the overexpressed esterase in cancer cells, TPE-QC could be efficiently activated in cancer cells rather than in normal cells, while the restoredfluorescence couldprecisely monitor the release of TPE-QC. Importantly, activated TPE-QC accumulated in both organelles of lysosome and mitochondria, resulting in enhanced anticancer potency. In vivo experiments demonstratedthat TPE-QCdisplayed efficient tumor microenvironment-activatable features and excellent tumor therapeutic effects through combinational CT and PDT. © 2022 Chinese Chemical Society. All right reserved.