Trojan Horse‐Like Nano‐AIE Aggregates Based on Homologous Targeting Strategy and Their Photodynamic Therapy in Anticancer Application

Abstract

Photodynamic therapy (PDT) has become a promising candidate for cancer theranostics; however, traditional photosensitizers (PSs) usually exhibit weak fluorescence and poor reactive oxygen species (ROS) generation efficiency when aggregated. Recently, aggregation-induced emission (AIE) luminogens have shown great potential in the development of novel PSs owing to their excellent aggregation-induced ROS generation (AIG-ROS) activity. However, there are still concerns that must be addressed. In this study, two near-infrared (NIR) emitters (PI and PTI) are synthesized with AIG-ROS characteristic. PTI exhibit a valuable redder emission with more effective intersystem crossing (ISC) process than PI. The two AIE-active PSs show excellent lipid droplet (LD)-specific targeting ability. The detailed therapeutic mechanism of PDT in LDs specificity is also investigated. The mechanism of oxidation of polyunsaturated fatty acids (PUFAs) in LDs to form toxic lipid peroxides (LPOs) and thereby causing cellular ferroptosis is confirmed first. Homologous targeting is also used to achieve tumor targeting via coating PSs with active cancer cell membranes. Biomimetic aggregates exhibit good targeting ability, and an improved PDT antitumor effect via AIG-ROS activity. These findings offer a clear route to develop advanced PSs with good targeting specificity. A template has also been provided for studying the therapeutic mechanism of AIE-active PSs.

Multiple Light-Activated Photodynamic Therapy of Tetraphenylethylene Derivative with AIE Characteristics for Hepatocellular Carcinoma via Dual-Organelles Targeting

“…Interestingly, JC-1 staining demonstrated that TPE-Py-OH could still induce dramatically mitochondrial damage in spite of tending to accumulate into LDs in Figure 4D. Singlet oxygen species produced by PDT can oxidize intracellular LDs to form lipid oxide or lipid peroxide [50]. The intracellular lipid peroxidation could initiate cellular ferroptosis, which can induce mitochondrial morphology disruption and depolarization in this process [51].…”

Metal-fluorouracil networks with disruption of mitochondrion enhanced ferroptosis for synergistic immune activation

“…As a result, large amount of reactive oxygen species (ROS) would be produced, resulting in the break of redox balance within cancer cells 47 - 49 , elimination of overexpressed glutathione (GSH) and the inactivation of glutathione peroxidase 4 (GPX4) protein. These would aggravate the excessive accumulation of lipid oxidation (LPOs) and trigger cancer cells ferroptosis (Figure 3 A) 50 - 51 . To validate the above proposed process, the intracellular concentration of Zn 2+ for Zn-Fu MNs treatment cancer cells was detected by ICP-MS, which showed the distinct increased Zn 2+ within Zn-Fu MNs treatment cells compared with PBS group, proving the Zn-Fu MNs entered the cells, successfully ( Figure S5 ).…”

“…To validate the above proposed process, the intracellular concentration of Zn 2+ for Zn-Fu MNs treatment cancer cells was detected by ICP-MS, which showed the distinct increased Zn 2+ within Zn-Fu MNs treatment cells compared with PBS group, proving the Zn-Fu MNs entered the cells, successfully ( Figure S5 ). Subsequently, we tested the cellular ROS production via incubating CT26 cells with Zn 2+ , Fu and Zn-Fu MNs, respectively, using 2',7'-dichlorofluorescin diacetate (DCFH-DA) as ROS indicator (Figure 3 B) 51 . From confocal fluorescent images, obvious fluorescence in green channel was observed in Zn 2+ treatment cells, indicating the intracellular ROS generation induced by Zn 2+ .…”

Aggregation-induced emission photosensitizer-based photodynamic therapy in cancer: from chemical to clinical

“…Currently, three methods are existed for introducing heavy atoms, one of which is to introduce halogen atom via covalent bond. For example, Tang's group synthesized an AIE-active model PS (PI) with good ROS production efficiency and NIR emission capability [ 78 ]. To enhance the ISC process, a thiophene ring was inlet into the backbone of PI by the heavy atom effect to obtain PTI.…”