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Photodynamic therapy (PDT) exerts its therapeutic effects by inducing apoptosis, necrosis, and microvascular damage in tumor cells, but it also causes inflammation and induces the expression of angiogenic factors, accelerating tumor metastasis and proliferation. In this study, aggregation-induced emission (AIE) photosensitizer (PS) for PDT was combined with the cyclooxygenase-2 (COX-2) inhibitor indomethacin (IMC) for cancer-selective imaging and more efficiency in inducing apoptosis in cancer cells. In detail, inhibition of COX-2-mediated AIE PS effectively targeted the Golgi apparatus (GA) of cancer cells to generate large amounts of reactive oxygen species (ROS) in situ, thereby exerting a PDT effect. Specifically, COX-2 and other key enzymes that trigger inflammation and metastasis were significantly inhibited. It had more potent anti-tumor activity (tumor inhibition rate of 64.32 %), as well as anti-metastatic and anti-proliferative effects compared to the use of usual AIE PS. [Display omitted] • TTPI was obtained by combining AIE-PS with the COX-2 inhibitor indomethacin. • TTPI precisely targeted COX-2 in the Golgi with high co-location coefficient. • PDT while inhibiting enzymes that trigger inflammation and metastasis such as COX-2. • The inhibition rate of TTPI in vivo was significantly increased to 64.32 %. [ABSTRACT FROM AUTHOR]

Schematic illustration of photodynamic therapy of TTQ-Th to accelerate ablating cancer cells. [Display omitted] • Altering functional group of compounds enhances the ability to target mitochondria. • TTQ-Th has desirable advantage of large stokes shifts and bright NIR emission. • The sufficient ROS generation of TTQ-Th upon photoexcitation can ablate cancer cells. • TTQ-Th inhibit copper-based enzyme activity to suppress metastasis of cancer cells. Abnormally high levels of copper in tumors stimulate malignant proliferation and migration of cancer cells, which proposes a formidable challenge for the thorough therapy of malignant tumors. In this work, we developed a reliable, mitochondria-targeted near-infrared aggregation-induced emission fluorescent probe, TTQ-Th, whose thiourea moiety specifically could recognize mitochondria even both upon loss of mitochondrial membrane potential or in fixated cells, and can capture copper overexpressed by tumor cells, leading to severe copper deficiency. In parallel, TTQ-Th can generate sufficient reactive oxygen species (ROS) upon photoexcitation, while copper deficiency inhibits expression of related copper-based enzymes, resulting in a decline in ATP production. Such energy deficiency, combined with reduced MMP and elevated oxidative stress can lead to critical cell oncosis. Both in vitro and intracellular experiments can illustrate that the elevated ROS has remarkable damage to tumor cells and contributes to the elimination of the primary tumor, while copper deficiency further hinder tumor cell migration and induces G0/G1 cell cycle arrest in a dose-dependent manner, which is an efficacious strategy for the treatment of malignant tumors. [ABSTRACT FROM AUTHOR]

Targeting the organelles that generate oxidative stress and implementing oxidative stress therapy is an essential and ambitious task. As an important subcellular organelle in eukaryotic cells, the endoplasmic reticulum (ER) is significant in mediating the direction of cell metabolism and apoptosis. To achieve the goal, we rationally designed and synthesized a photosensitizer named TTQ-ER with aggregation-induced emission (AIE) characteristics. Such a probe connects the AIE-fluorophore to the glibenclamide backbone, which enables TTQ-ER to specifically target the ER and promote emission in the near-infrared region, avoiding the negative impact of autofluorescence in organisms. Meanwhile, TTQ-ER has a large stokes shift, excellent anti-photobleaching properties, and sufficient 1O 2 production (8.85-fold of Ce6). Apoptosis assay and cell migration assay further verified that excessive reactive oxygen species production by TTQ-ER in cancer cells could promote oxidative stress in the ER microenvironment and disrupt the normal biological function of ER, thus causing elevated local lipid peroxidation and inducing apoptosis in cancer cells. Consequently, this work offers informative ideas for designing a newly generation of photosensitizers to achieve accurate photodynamic therapy. Schematic diagram of TTQ-ER promoting apoptosis of cancer cells. [Display omitted] • TTQ-ER possesses bright NIR emission, large stokes shifts and precise ER targeting. • Significant ER-targeted specificity (Rr = 0.903). • Extremely high generation yield of 1O 2 (8.85-fold that of Ce6). • Superior photodynamic ablation of cancer cells. [ABSTRACT FROM AUTHOR]

Photodynamic therapy (PDT) combined with critical organelle targeting can maximize ablation of malignant tumors, which is a desirable route against cancer. However, the short excitation/emission wavelengths of conventional photosensitizers (PSs), the inefficient production of reactive oxygen species (ROS) and the inevitable aggregation-induced quenching phenomenon have restricted their development. Herein, we developed and synthesized a set of photoactivated fluorescent probes named MoTQu and MeTQu with aggregation-induced emission properties. The both of fluorescent probes have merits of bright near-infrared fluorescence emission, large stokes shift and enhanced intramolecular charge transfer attributed to the synergistic interaction of strong donor and acceptor of molecular. In addition, the optimal PS named MoTQu not only possesses superior anti-photobleaching, biocompatibility and extremely high-level ROS generation efficiency, on the other hand, can time-responsive target mitochondria and lysosomes in living cells to cause lysosomal dysfunction by generating large amount of ROS in situ under photoexcitation, subsequently targeting mitochondria through the positive electrical properties of the quinoline fraction, further inducing and promoting cancer cell damage and irreversible apoptosis. Consequently, we are convinced that MoTQu can be a powerful tool to foster the development of image-guided PDT. [Display omitted] • MoTQu has merit of time-responsive mitochondria and lysosomes targeting. • MoTQu have desirable advantages of large stokes shifts and bright NIR emission. • The sufficient ROS generation of MoTQu upon photoexcitation can ablate cancer cells. • Tiny doses of MoTQu under photoexcitation could suppress metastasis of cancer cells. [ABSTRACT FROM AUTHOR]

The label-free localized surface plasmon resonance (LSPR) detection technique has been identified as a powerful means for in situ investigation of biological processes and localized chemical reactions at single particle level with high spatial and temporal resolution. Herein, a core-satellites assembled nanostructure of Au50@Au13 was designed for in situ detection and intracellular imaging of telomerase activity by combining plasmonic resonance Rayleigh scattering spectroscopy with dark-field microscope (DFM). The Au50@Au13 was fabricated by using 50 nm gold nanoparticles (Au50) as core and 13 nm gold nanoparticles (Au13) as satellites, both of them were functionalized with single chain DNA and gathered proximity through the highly specific DNA hybridization with a nicked hairpin DNA (O1) containing a telomerase substrate (TS) primer as linker. In the presence of telomerase, the telomeric repeated sequence of (TTAGGG)n extended at the 3'-end of O1 would hybridized with its complementary sequences at 5'-ends. This led the telomerase extension product of O1 be folded to form a rigid hairpin structure. As a result, the Au50@Au13 was disassembled with the releasing of O1 and Au13-S from Au50-L, which dramatically decreased the plasmon coupling effect. The remarkable LSPR spectral shift was observed accompanied by a detectable color change from orange to green with the increase of telomerase activity at single particle level with a detection limit of 1.3 × 10-13 IU. The ability of Au50@Au13 for in situ imaging intracellular telomerase activity, distinguishing cancer cells from normal cells, in situ monitoring the variation of cellular telomerase activity after treated with drugs were also demonstrated. [ABSTRACT FROM AUTHOR]

[Display omitted] • A Novel NIR AIEgen (MTOQS) synthesized for efficient ROS production. • MTOQS has a killing effect on cancer cells with less damage to normal cells. • Induces endoplasmic reticulum-mitochondria dual oxidative stress. • MTOQS could affect energy metabolism and alter the tumor microenvironment. • MTOQS switches on apoptotic pathways in multiple ways. Organelle-targeted photodynamic therapy has been increasingly investigated in recent decades, but little attention has been paid to the damage caused to other non-primary target organelles during the course of action, even though these non-primary target organelles may play a substantial role in inhibiting the growth of cancer cells. In this contribution, we report an AIE-type strong endoplasmic reticulum-targeted luminogen (MTOQS) with a distorted structure, which is efficient in producing ROS both in cellular and non-cellular environment, causing an effective reduction of high levels of GSH and MDA in cancer cells through the efficient accumulation of intracellular ROS, and the levels of ATP, l -lactic acid, anti-apoptotic factor Bcl-2 and apoptotic protein caspase-3 were determined. Through the identification of these markers, it was evidenced that MTOQS -induced dual organelle oxidative stress could diminish the degree of oxidative phosphorylation and glycolysis in cancer cells and trigger an alteration in the culture environment of cancer cells, while causing damage to the endoplasmic reticulum and mitochondria through multiorganelle oxidative stress, turning on the pathway of apoptosis and consequently driving cancer cells to apoptosis. [ABSTRACT FROM AUTHOR]

The aggregation-induced emission photosensitizers (AIE-PSs) manifest a multitude of notable superiorities in terms of high specificity to organelles, high-efficient singlet oxygen (1O 2) generation as well as enhanced fluorescence intensity, which provides a feasible approach to overcome the problems such as the insufficient generation of reactive oxygen species (ROS) caused by grave aggregation-induced quenching (ACQ) and the lack of specific targeting existing in traditional PSs, but extremely challenging. Herein, a series of near-infrared (NIR) AIE luminogens (AIEgens) for targeting mitochondrial was devised and synthesized by regulating the D-A intensity assembly molecular engineering, which fabricating a progressively stronger intermolecular charge transfer (ICT) state to accelerate highly effective intersystem crossing (ISC) of excited electrons by the synergistic effect of thiophene and quinolinium. Impressively, the optimal NIR AIE-PS (DTTVQ-OH) revealed excellent photostability, biocompatibility, precise mitochondria targeting, extremely high generation yield of 1O 2 (4.9-fold that of Rose Bengal) and superior phototoxicity in living HepG2 cells. Furthermore, apoptosis assay and cell migration experiment further demonstrated that DTTVQ-OH could efficaciously restrain cell proliferation and induce/speed up cancer cell death. Moreover, DTTVQ-OH can selectively distinguish cancer cells and normal cells by difference of fluorescence intensity in high resolution without the assist of any extra targeting ligands. As a consequence, this work provides a rational and practicable strategy for the specific targeted molecular engineering of AIE-PSs, which gives impetus to the development of fluorescence imaging-guided photodynamic therapy fields. Multifunctional nano-photosensitizer was used for mitochondrial-targeting photodynamic ablation of liver cancer cells. [Display omitted] • A mitochondria targeted NIR AIE nanomaterial (DTTVQ-OH) was synthesized by a simple three-part fragment assembly molecular engineering. • DTTVQ-OH possesses desirable merits especially precise mitochondrial targeting and efficient 1O 2 generation. • DTTVQ-OH could selectively accumulate in cancer cells rather than normal cells without the aid of any additional targeting ligands. • As a nanoparticle PS, DTTVQ-OH was successfully used for photodynamic ablation in living HepG2 cells under white light irradiation. [ABSTRACT FROM AUTHOR]

Multifunctional nano-photosensitizer was used for high-fidelity imaging of lipid droplets and photodynamic ablation of liver cancer cells. • A lipophilic NIR AIE nanomaterial (TTI) was designed and prepared. • TTI was applied to specifically 'light up' and high-fidelity dynamic tracking LDs. • In the PBS solution, TTI exhibited extremely efficient 1O 2 quantum yield. • TTI was successfully used for photodynamic ablation cancer cells. Near-infrared (NIR) aggregation-induced emission (AIE) nanomaterials, with organelles targeted-imaging ability and effective reactive oxygen species (ROS) generation nature, are highly desirable photosensitizers (PSs) for fluorescence imaging-guided photodynamic therapy (PDT), but it remains challenging. Herein, a NIR AIE luminogens (AIEgens, TTI) was designed and synthesized using three-fragmentary assembly molecular engineering, which was used for intracellular lipid droplets (LDs) high-fidelity dynamic tracking (Pearson's coefficient of 0.95) due to its strong lipophilic nature (ClogP of 8.34), large Stokes shifts (170 nm), excellent photostability and good biocompatibility. Meanwhile, TTI self-assembled nanoparticles with an average diameter of 196.57 nm exhibited extremely high-efficient singlet oxygen (1O 2) generation efficiency (with up to 85.16% of quantum yield) in PBS solution. In addition, the TTI as a desired PS revealed good phototoxicity for living HepG2 cells under white light irradiation. Moreover, the live/dead cells co-staining image, flow cytometry and scratch wound healing assays indicated that TTI could effectively inhibit the proliferation and cause/induce cells apoptosis, which eventually led to the death of HepG2 cells. Therefore, this work provides a useful strategy for LDs-targeting molecular engineering and highlights the potential of organic nanoparticles PSs drug in biomedical and fluorescence imaging-guided PDT fields. [ABSTRACT FROM AUTHOR]

• O 2 self-sufficient enhanced PDT efficiency anti-hypoxia effect. • Wide-spectrum cancer cell discrimination without the aid of any extra cancer cell-specific targeting ligands. • Mitochondria-specific targeting enhances therapeutic efficiency of PDT. The severe hypoxia in solid tumor and the accurate discrimination between cancer and normal cells gravely restrict the application of fluorescence imaging-guided photodynamic therapy (PDT), although this cancer-therapy modality has significant superiorities in terms of precise visualization of the location of photosensitizers (PSs) in tumor tissue as well as noninvasive and reliable treatment. A convenient and universal fluorescence system featuring Type I reactive oxygen species (ROS) based on free radicals, wide-spectrum cancer cell discrimination and distinctive aggregation-induced emission (AIE) characteristics could offer a feasible approach to resolve the problems above, which is yet extremely challenging. Herein, we propose a series of electron-rich anion-π+ AIE-active luminogens (AIEgens) fabricating increasingly stronger intermolecular charge transfer (ICT) state to promote highly efficient intersystem crossing for boosting Type I ROS generation. Moreover, MeOTPPM has priority to enter cancer cells with better plasma membrane permeability due to the strongest binding force with water molecules. This work serves as a pioneering reference for rationally constructing Type I-based purely organic PSs to overcome tumor hypoxia defects in PDT and selectively targeting and ablating cancer cells over normal cells without the aid of any extra cancer cell-specific targeting ligands. [ABSTRACT FROM AUTHOR]