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Photodynamic therapy (PDT) is a pioneering and effective anticancer modality with low adverse effects and high selectivity. Hypochlorous acid or hypochlorite (HClO/ClO−) is a type of inflammatory cytokine. The abnormal increase of ClO− in tumor cells is related to tumor pathogenesis and may be a "friend" for the design and synthesis of responsive phototherapy agents. However, preparing responsive phototherapy agents for all-in-one noninvasive diagnosis and simultaneous in situ therapy in a complex tumor environment is highly desirable but still remains an enormously demanding task. An acceptor-π bridge-donor-π bridge-acceptor (A-π-D-π-A) type photosensitizer TPTPy was designed and synthesized based on the phenothiazine structure which was used as the donor moiety as well as a ClO− responsive group. TPTPy was a multifunctional mitochondria targeted aggregation-induced emission (AIE) photosensitizer which could quickly and sensitively respond to ClO− with fluorescence "turn on" performance (19-fold fluorescence enhancement) and enhanced type I reactive oxygen species (ROS) generation to effectively ablate hypoxic tumor cells. The detection limit of TPTPy to ClO− was calculated to be 185.38 nM. The well-tailored TPTPy anchoring to mitochondria and producing ROS in situ could disrupt mitochondria and promote cell apoptosis. TPTPy was able to image inflammatory cells and tumor cells through ClO− response. In vivo results revealed that TPTPy was successfully utilized for PDT in tumor bearing nude mice and exhibited excellent biological safety for major organs. A win-win integration strategy was proposed to design a tumor intracellular ClO− responsive photosensitizer TPTPy capable of both type I and type II ROS production to achieve photodynamic therapy of tumor. This work sheds light on the win-win integration design by taking full advantage of the characteristics of tumor microenvironment to build up responsive photosensitizer for in situ PDT of tumor. [Display omitted] • An AIE photosensitizer TPTPy for ClO− detection and follow-on PDT is designed. • TPTPy can target mitochondria and generate type I and type II ROS for PDT. • TPTPy can detect ClO− with fluorescence turn on and enhanced type I ROS generation. • TPTPy can detect endogenous ClO− in inflammatory cells and tumor cells. [ABSTRACT FROM AUTHOR]

Fluorescence imaging-guided photodynamic therapy (PDT) is considered as an ideal alternative strategy to treat tumors. However, insufficient supply of oxygen in solid tumor tissue, aggregation-caused quenching (ACQ) of photosensitizers (PSs), poor targeting-specificity of cancer cells and short wavelengths of emission are representative obstacles for effective PDT. In this paper, three D-π-A structured PSs TSB-OH , TSBPy-OH , TSBPy-DNT with aggregation induced emission (AIE) properties and integrated type I and type II ROS generation were synthesized by modulating distinct acceptor units. Among them, TSBPy-OH is optimal with multiple advantages including near-infrared emission, good biocompatibility, remarkably intracellular ROS production ability, mitochondria targeting capability inducing cell apoptosis and enhancing PDT, and long-term tumor retention ability for imaging-guided photodynamic therapy. More importantly, efficient in vitro cancer cells damage, in vivo tumor ablation and ignorable damage in major organs during PDT are demonstrated, suggesting potential capability of TSBPy-OH in safe and effective fluorescence imaging-guided PDT. This successful example of AIE theranostics design would provide a reference for the modification of D-π-A structure organic AIEgens. [Display omitted] • Three organic photosensitizers with AIE characteristic were developed. • TSBPy-OH exhibited excellent type Ⅰ and type Ⅱ ROS generation ability. • TSBPy-OH showed mitochondria targeting capability and could induce cell apoptosis. • TSBPy-OH could effectively inhibit tumor growth and had good biological safety. [ABSTRACT FROM AUTHOR]

[Display omitted] • Four organic photosensitizers with AIE characteristic were developed. • TSPy-B exhibited excellent ROS (type I and type II) generation ability. • TSPy-B showed biotin receptor and mitochondria dual-targeted capability in cells. • TSPy-B could effectively inhibit tumor growth and had good biological safety. Rational design of organelle targeted therapeutic platform in where the drug can be targeted to destroy tumor cells as much as possible, is one of the effective ways to improve the therapeutic outcomes and minimize the cytotoxicity to normal cells. Here, photosensitizer TSPy-B with aggregation-induced emission (AIE) feature, biotin receptor and mitochondria dual-targeted capability, and high reactive oxygen species (ROS) generation efficiency was designed for fluorescence imaging guided photodynamic therapy (PDT) by linking biotin group to D-π-A type AIE dyes via ester bonds. Notably, cell imaging experiments showed that TSPy-B could selectively target tumor cells with biotin receptor overexpression and further exhibit mitochondria targeting ability. The in vitro anticancer mechanism confirmed that after cell internalization, TSPy-B localized in the mitochondrial site and produced ROS resulting in mitochondrial dysfunction and cell death. ROS generation experiments showed that TSPy-B could simultaneously produce 1O 2 and highly toxic free radicals which not depended on the oxygen level of solid tumor. The cell killing effect of TSPy-B was also confirmed in hypoxic culture model. In vivo photodynamic therapy experiments demonstrated that TSPy-B could effectively inhibit tumor growth and had good biological safety. This work provides a choice for development of highly targeted photosensitizers for clinical fluorescence imaging guided PDT. [ABSTRACT FROM AUTHOR]

[Display omitted] • Four homologous luminogens with AIE characteristics through acceptor substitution engineering were developed. • The four photosensitizers showed excellent ROS generation capacities and different organelle targeting abilities. • TBVP targeting cellular membrane exhibited the strongest antitumor PDT efficiency. Photodynamic therapy (PDT) is a promising noninvasive treatment for cancer. Researchers have focused on improving the therapeutic effects of PDT in recent years. Subcellular organelles are the building blocks of cells, and their destruction can lead to cell dysfunction or even death. Photosensitizers (PSs) with precise organelle targeting capacity can not only kill cancer cells effectively but also help reduce PS dose, minimize side effects, and avoid drug resistance. Herein, four homologous luminogens with aggregation-induced emission (AIE) characteristics through acceptor substitution engineering are designed and synthesized to specifically anchor to mitochondria, cell membrane and lysosome through slight structural tweaks, and reactive oxygen species (ROS) are efficiently produced under light irradiation, which significantly enhance the therapy efficacy of PDT. Notably, biological studies have shown that membrane-targeted PS, TBVP exhibits more powerful therapeutic effects than other three PSs (TBPy , TBPy-Bu and TBPy-TA) at the same concentration. The highly effective anti-tumor activity of TBVP was evaluated successfully in vitro and in vivo. In addition, TBVP can promote cell autophagy to induce cell death. We thus believe the anchoring organelles approach described here represents an attractive therapeutic approach in photodynamic therapy. [ABSTRACT FROM AUTHOR]

Photodynamic therapy (PDT) is a promising treatment for cancer, but still faces challenges. For example, the residual photosensitizers (PSs) can cause toxic effects on normal tissues. Thus, it is of great importance to change the PS into safe compounds in or after PDT process. In this work, a novel PS NTPy was synthesized and successfully applied for cancer therapy. NTPy with aggregation-induced emission (AIE) characteristics shows high reactive oxygen species generation efficiency and exhibits a strong fluorescence emission in 678 nm. In addition, NTPy shows excellent mitochondria targeting capacity. In hypoxic microenvironment, NTPy is degraded into TPy via the reduction caused by nitroreductase. TPy shows very little PDT activities and low fluorescence emission. Therefore, NTPy can detect the hypoxic microenvironment of tumor through fluorescence "turn-off" response. More importantly, NTPy can reduce the side effects of PS on normal tissues after effective PDT treatment. This work provides a new strategy for intelligent PDT treatment and increases the biological safety of PDT. • A new aggregation-induced emission (AIE) photosensitizer NTPy was developed. • NTPy showed excellent mitochondria targeting and high ROS generation capacities. • NTPy could be degraded into TPy via the reduction by NTR in hypoxic condition. • TPy showed very little PDT activity and low fluorescence emission. [ABSTRACT FROM AUTHOR]

Development of multifunctional probes that can be simultaneously utilized for both efficient hydrogen sulfide detection and photodynamic therapy in cancer cells is in high demand but remains worldwide challenge. Herein, a fluorescent probe DB2T based on a BODIPY structure for H 2 S fluorescence "turn-on" detection together with light sensitive anticancer capacity has been designed and synthesized. The probe DB2T features high selectivity towards H 2 S, excellent low detection limit (6.39 nM), and good biocompatibility. Importantly, the probe DB2T has been satisfactorily applied in fluorescence imaging of exogenous H 2 S in zebrafish, and successfully employed in fluorescence imaging of endogenous H 2 S in HCT116 cell and tumor tissues. Moreover, evaluation of the phototherapy effect demonstrates that the probe DB2T performs well as a photosensitizer for photodynamic ablation of HCT116 cancer cells upon white light irradiation. This work should facilitate significant advances in rational design of fluorescence systems for H 2 S detection and even in the diagnosis and treatment of H 2 S related diseases. [Display omitted] • A novel fluorescent probe DB2T for hydrogen sulfide detection was developed. • DB2T can detect H 2 S with excellent selectivity and low detection limit (6.39 nM). • DB2T can detect endogenous H 2 S in HCT116 cell with fluorescence turn-on. • DB2T performs well for photodynamic therapy of HCT116 cancer cells. [ABSTRACT FROM AUTHOR]