Endoplasmic Reticulum-Targeted Aggregation-Induced Emission Luminogen for Synergetic Tumor Ablation with Glibenclamide

Abstract

Photodynamic therapy based on fluorescence illumination of subcellular organelles and in situ bursts of reactive oxygen species (ROS) has been recognized as a promising strategy for cancer theranostics. However, the short life of ROS and unclarified anticancer mechanism seriously restrict the application. Herein, we rationally designed and facilely synthesized a 2,6-dimethylpyridine-based triphenylamine (TPA) derivative TPA-DMPy with aggregation-induced emission (AIE) features and production of type-I ROS. Except for its selective binding to the endoplasmic reticulum (ER), TPA-DMPy, in synergy with glibenclamide, a medicinal agent used against diabetes, induced significant apoptosis of cancer cells in vitro and in vivo. Additionally, TPA-DMPy greatly incited the release of calcium from ER upon light irradiation to further aggravate the depolarization of ER membrane potential caused by glibenclamide, thus inducing fatal ER stress and crosstalk between ER and mitochondria. Our study extends the biological design and application of AIE luminogens and provides new insights into discovering novel anticancer targets and agents.

Two-Photon Absorption Aggregation-Induced Emission Luminogen/Paclitaxel Nanoparticles for Cancer Theranostics

“…In the pertinent context, optimal probes for MPFI-guided chemotherapy must exhibit several inherent characteristics, including elevated fluorescence brightness upon near-infrared excitation, exceptional photostability, and commendable biocompatibility. , However, most of the conventional probes usually suffer from fluorescence quenching, owing to the hydrophobic nature and relatively planar structures of probes, which cause intense intermolecular π–π stacking and induce aggregate within a physiological environment. , Remarkably, aggregation-induced emission (AIE) furnishes an exceptionally potent mechanism to overcome this hurdle. , Bioprobes endowed with AIE characteristics remain nonemissive or exhibit weak emission in their single-molecule state. However, they are prompted to emit intensely upon the formation of aggregated states, facilitated by the mechanism of intramolecular motion restriction (RIM). , Moreover, lipid-encapsulated nanoplatforms including MPFI-active AIE probes and therapeutic drugs such as paclitaxel (PTX), doxorubicin, and camptothecin to form water-soluble nanoparticles (NPs) are utilized to prolong blood circulation time and improve accumulation in tumor-seated tissues in vivo via the enhanced permeability and retention (EPR) effect, which could significantly mitigate toxicity while concurrently preserving anticancer efficacy. − Notwithstanding the great potential of MPFI-active AIE luminogens (AIEgens) in this area, to the best of our knowledge, such AIE bioprobes encapsulating nanoplatforms cooperation with chemotherapy have rarely been reported to date. , This thus motivated us to pioneer multifunctional nanoplatforms simultaneously possessing effective near-infrared excited MPFI and superb chemotherapy capability.…”