Mitochondria-Targeted Cancer Therapy Using an Endogenous Stimuli-Responsive Prodrug With Aggregation-Induced-Emission Features

Abstract

Theranostic agents derived from aggregation-induced emission luminogens (AIEgens) offer significant potential, yet platforms that provide controlled drug release, organelle-specific action, and self-reporting capability are highly desired. Herein, we report a mitochondria-targeted prodrug system that integrates an AIE fluorophore with excited-state intramolecular proton transfer (ESIPT) characteristics, covalently linked to the anticancer drug dasatinib. The amphiphilic prodrug self-assembled into nanoparticles of around 210 nm with a spherical morphology. The probe is initially non-fluorescent due to ESIPT inhibition. Following cellular internalization, intracellular esterases cleave the carbonate linker, initiating two simultaneous processes: (1) the cytosolic release of dasatinib to inhibit proliferation-associated tyrosine kinases, and (2) the restoration of ESIPT and subsequent aggregation of the fluorophore, yielding a ratiometric fluorescence turn-on signal for real-time monitoring. The liberated probe, appended with a triphenylphosphine moiety, then selectively targets mitochondria, where it generates reactive oxygen species (ROS), inducing mitochondrial damage and promoting apoptosis. This combination of cytosolic kinase inhibition and mitochondria-targeted ROS production creates a powerful synergistic anticancer effect, demonstrating significantly enhanced efficacy over dasatinib alone. This multifunctional design pioneers a theranostic approach that merges precise drug activation, dynamic imaging, and organelle-specific therapy.