The rational design of cancer theranostics with natural diagnostic information and therapeutic behavior has been considered to be a big challenge, since common theranostics from photothermal and photodynamic therapy need to be activated with external stimuli of photoirradiation to enable the chemotherapeutic effects. In this contribution, we have designed and synthesized a series of simple theranostic agents, TPA-N-n (n = 4, 8, 12), which could accumulate at the tumor site over 48 h and indicate superior antiproliferative performance in vivo. TPA-N-n was constructed with electron donor triphenylamine-acceptor benzothiadiazole-mitochondria-targeting moiety pyridinium. Complex TPA-N-8 indicated the best cytotoxicity to cancerous HeLa cells, with an IC50 value of 4.3 μM, and could self-assemble to a nanosphere with a size of 161.2 nm in the DMSO/PBS solution. It is worth noting that TPA-N-8 could accumulate in the mitochondria and produce major ROS species O2•- and OH• as well as small amounts of 1O2 without photoirradiation. Oxidative DNA damage is initiated due to the imbalance of intracellular redox homeostasis from the significant ROS storm. Multimodal synergistic therapy for HeLa cells was activated, as the PINK1-mediated mitophagy from the damaged mitochondria and DNA damage responsive (DDR) induced necroptosis and autophagy. This work not only provided a successful D-A type theranostic agent with superior anticancer performance from multimodal synergistic therapy but also further demonstrated the high efficacy of a mitochondria-targeting strategy for cancer treatment.
Keywords: aggregation-induced emission; donor−acceptor structure; mitochondria-targeting; multimodal cancer therapy; self-assembly theranostic nanosphere.