Aggregation-Induced Emission-Active Organic Nanoagent with High Photothermal Conversion Efficiency for Near-Infrared Imaging-Guided Tumor Photothermal Therapy.

Photothermal therapy (PTT) provides a great prospect for noninvasive cancer therapy. However, it is still highly challenging to construct photothermal agents (PTAs) with the desired performances for imaging-guided PTT applications. Herein, a D-A-D-type naphthalene diamine (NDI)-based photothermal nano-PTAs NDS-BPN NP with near-infrared region (NIR) emission at 822 nm, aggregation-induced emission (AIE), high photothermal conversion efficiency (55.05%), and excellent photothermal stability is successfully designed and prepared through a simple two-step engineering method by using a new AIE molecule NDS-BPN and DSPE-PEG2000 as precursors. The prepared PTT nanoagents NDS-BPN NPs have been further applied for efficient photothermal ablation of cancer cells in vitro and also achieved the NIR fluorescent image-guided PTT tumor therapy in vivo with satisfactory results. We believe that this work provides an attractive NIR AIE NDI-based nano-PTA for the phototherapy of tumors as well as develops the construction strategy of NDI molecular-based photothermal nanoagents with desired performances for imaging-guided PTT.

A series of tetraphenylene-acetonitrile AIE compounds with D-A-D' structure for drugs delivery systems of paclitaxel: Synthesis, structure-activity relationship and anti-tumors effect.

Aggregation-induced emission (AIE) materials are attracting great attention in biomedical fields such as sensors, bioimaging, and cancer treatment, et al. due to their strong fluorescence emission in the aggregated state. In this contribution, a series of tetraphenylene-acetonitrile AIE compounds with D-A-D' structures were synthesized by Suzuki coupling reaction and Knoevenagel condensation, and their relationship of chemical structure and fluorescence properties was investigated in detail, among which TPPA compound was selected as the monomer owing to the longest emission wavelength at about 530 nm with low energy band gap ΔE 3.09 eV of neutral TPPA and 1.43 eV of protonated TPPA. Novel amphiphilic AIE PEG-TA copolymers were prepared by RAFT polymerization of TPPA and PEGMA with about 1.44×104 Mw and narrow PDI, and the molar ratio of TPPA in the PEG-TA1 and PEG-TA2 copolymers was about 23.4 % and 29.6 %. The as-prepared PEG-TA copolymers would self-assembled in aqueous solution to form core-shell structures with a diameter of 150-200 nm, and their emission wavelength could reversibly convert from 545 nm to 650 nm with excellent pH sensitivity. The CLSM images showed that the PEG-TA FONs and PTX drugs-loaded PTX-TA FONs could be endocytosed by cells and mainly enriched in the cytoplasm, and CCK-8 results showed that the PEG-TA FONs had excellent biocompatibility but PTX-TA FONs had high inhibition ratio for A549 cells, moreover, the flow cytometry also showed that PTX-TA FONs could result in the apoptosis of A549 cells with some extent anti-tumor effect.

Development of an AIE-active fluorescent probe for the simultaneous detection of Al3+ and viscosity and imaging in Alzheimer's disease model.

Alzheimer's disease is associated both with imbalances in Al3+ production and changes in viscosity in cells. Their simultaneous measurement could therefore provide valuable insights into Alzheimer's disease pathology. Their simultaneous measurement would therefore be of great value in investigating the pathological mechanism of Alzheimer's disease. We designed a fluorescent probe YM2T with AIE effect that is capable of selectively responding to Al3+ by fluorescence colormetrics and to viscosity by fluorescence "turn on" modes. Additionally, Al3+ and viscosity were simultaneously detected in PC12 cells using the low cytotoxic probe YM2T via blue and green fluorescence channels. More importantly, the YM2T probe was used to image mice with AD. Hence, the YM2T probe shows potential as a useful molecular instrument for studying the pathological impact of Al3+ and viscosity.

All-in-One Alkaline Phosphatase-Response Aggregation-Induced Emission Probe for Cancer Discriminative Imaging and Combinational Chemodynamic-Photodynamic Therapy.

Currently, specific cancer-responsive fluorogenic probes with activatable imaging and therapeutic functionalities are in great demand in the accurate diagnostics and efficient therapy of malignancies. Herein, an all-in-one strategy is presented to realize fluorescence (FL) imaging-guided and synergetic chemodynamic-photodynamic cancer therapy by using a multifunctional alkaline phosphatase (ALP)-response aggregation-induced emission (AIE) probe, TPE-APP. By responding to the abnormal expression levels of an ALP biomarker in cancer cells, the phosphate groups on the AIE probe are selectively hydrolyzed, accompanied by in situ formation of strong emissive AIE aggregates for discriminative cancer cell imaging over normal cells and highly active quinone methide species with robust chemodynamic-photodynamic activities. Consequently, the activated AIE probes can efficiently destroy cancer cell membranes and lead to the death of cancer cells within 30 min. A superior efficacy in cancer cell ablation is demonstrated in vitro and in vivo. The cancer-associated biomarker response-derived discriminative FL imaging and synergistic chemodynamic-photodynamic therapy are expected to provide a promising avenue for precise image-guided cancer therapy.

AIE luminogen labeled polymeric micelles for biological imaging and chemotherapy.

In this study, an amphiphilic polymer FA-CS-DBA-CHO with aggregation-induced emission (AIE) feature was prepared by introducing 4-(diphenylamino)benzaldehyde derivative (DBA-CHO), imine bond and folic acid (FA) to the molecular structure of chitosan (CS). The amphiphilicity drove the polymer to self-assemble into micelles, and paclitaxel (PTX) could be solubilized in the hydrophobic core. Due to the excellent AIE effect, FA-CS-DBA-CHO exhibited strong cellular imaging capability. The pH-sensitive imine bond in the polymer allowed for accurate drug release in acidic environment. Both in vitro and in vivo studies demonstrated that the PTX-loaded FA-CS-DBA-CHO micelles could significantly inhibit the growth of tumor cells but without any notable toxicity. This micellar system was excellent carrier for bioimaging and chemotherapeutic drug delivery.

Biotin-conjugated Ru(II) complexes with AIE characteristics as mitochondria-targeted photosensitizers for enhancing photodynamic therapy by disrupting cellular redox balance.

The potential use of Ru(II) complexes as photosensitizers (PSs) in photodynamic therapy (PDT) has gained significant attention. In comparison with fluorophores with aggregation-caused quenching (ACQ), fluorophores with aggregation-induced emission (AIE) characteristics exhibit sustained fluorescence and dispersibility in aqueous solutions. PSs with AIE characteristics have received much attention in recent years. Herein, we reported two novel biotin-conjugated Ru(II) polypyridyl complexes (Ru1 and Ru2) with AIE characteristics. When exposed to 460 nm (10 mW cm-2) light, Ru1 and Ru2 exhibited outstanding photostability and photocatalytic activity. Ru1 and Ru2 could efficiently generate singlet oxygen and induce pUC19 DNA photolysis when exposed to 460 nm light. Interestingly, both Ru1 and Ru2 also functioned as catalysts for NADH oxidation when exposed to 460 nm light. The presence of biotin fragments in Ru1 and Ru2 enhanced the specific uptake of these complexes by tumor cells. Both complexes showed minimal toxicity to selected cells in the dark. Nevertheless, the phototoxicity of both complexes significantly increased upon 460 nm light irradiation for 15 min. Further experiments revealed that Ru2 primarily accumulated in mitochondria and might bind to mitochondrial DNA. Under 460 nm light irradiation, Ru2 induced the generation of reactive oxygen species (ROS) and NADH depletion disrupting intracellular redox homeostasis in A549 cells, activating the mitochondrial apoptosis pathway resulting in up-regulation of apoptotic marker caspase-3, effectively damaged A549 cell DNA and arrested A549 cell cycle in the S phase. In vivo anti-tumor experiments were conducted to assess the effects of Ru2 on tumor growth in A549 tumor-bearing mice. The results showed that Ru2 effectively inhibited tumor growth under 460 nm light irradiation conditions. These findings indicate that Ru2 has great potential as a targeted photosensitizer for mitochondrial targeting imaging and photodynamic therapy of tumors.

Engineered Extracellular Vesicles Expressing Siglec-10 Camouflaged AIE Photosensitizer to Reprogram Macrophages to Active M1 Phenotype and Present Tumor-Associated Antigens for Photodynamic Immunotherapy.

Cancer immunotherapy has attracted considerable attention due to its advantages of persistence, targeting, and ability to kill tumor cells. However, the efficacy of tumor immunotherapy in practical applications is limited by tumor heterogeneity and complex tumor immunosuppressive microenvironments in which abundant of M2 macrophages and immune checkpoints (ICs) are present. Herein, two type-I aggregation-induced emission (AIE)-active photosensitizers with various reactive oxygen species (ROS)-generating efficiencies are designed and synthesized. Engineered extracellular vesicles (EVs) that express ICs Siglec-10 are first obtained from 4T1 tumor cells. The engineered EVs are then fused with the AIE photosensitizer-loaded lipidic nanosystem to form SEx@Fc-NPs. The ROS generated by the inner type-I AIE photosensitizer of the SEx@Fc-NPs through photodynamic therapy (PDT) can convert M2 macrophages into M1 macrophages to improve tumor immunosuppressive microenvironment. The outer EV-antigens that carry 4T1 tumor-associated antigens directly stimulate dendritic cells maturation to activate different types of tumor-specific T cells in overcoming tumor heterogeneity. In addition, blocking Siglec-10 reversed macrophage exhaustion for enhanced antitumor ability. This study presents that a combination of PDT, immune checkpoints, and EV-antigens can greatly improve the efficiency of tumor immunotherapy and is expected to serve as an emerging strategy to improve tumor immunosuppressive microenvironment and overcome immune escape.

An AIE Metal Iridium Complex: Photophysical Properties and Singlet Oxygen Generation Capacity.

Photodynamic therapy (PDT) has garnered significant attention in the fields of cancer treatment and drug-resistant bacteria eradication due to its non-invasive nature and spatiotemporal controllability. Iridium complexes have captivated researchers owing to their tunable structure, exceptional optical properties, and substantial Stokes displacement. However, most of these complexes suffer from aggregation-induced quenching, leading to diminished luminous efficiency. In contrast to conventional photosensitizers, photosensitizers exhibiting aggregation-induced luminescence (AIE) properties retain the ability to generate a large number of reactive oxygen species when aggregated. To overcome these limitations, we designed and synthesized a novel iridium complex named Ir-TPA in this study. It incorporates quinoline triphenylamine cyclomethylated ligands that confer AIE characteristics for Ir-TPA. We systematically investigated the photophysical properties, AIE behavior, spectral features, and reactive oxygen generation capacity of Ir-TPA. The results demonstrate that Ir-TPA exhibits excellent optical properties with pronounced AIE phenomenon and robust capability for producing singlet oxygen species. This work not only introduces a new class of metal iridium complex photosensitizer with AIE attributes but also holds promise for achieving remarkable photodynamic therapeutic effects in future cellular experiments and biological studies.

A recent update on development, synthesis methods, properties and application of natural products derived carbon dots.

Natural resources are practically infinitely abundant in nature, which stimulates scientists to create new materials with inventive uses and minimal environmental impact. Due to the various benefits of natural carbon dots (NCDs) from them has received a lot of attention recently. Natural products-derived carbon dots have recently emerged as a highly promising class of nanomaterials, showcasing exceptional properties and eco-friendly nature, which make them appealing for diverse applications in various fields such as biomedical, environmental sensing and monitoring, energy storage and conversion, optoelectronics and photonics, agriculture, quantum computing, nanomedicine and cancer therapy. Characterization techniques such as Photoinduced electron transfer, Aggregation-Induced-Emission (AIE), Absorbance, Fluorescence in UV-Vis and NIR Regions play crucial roles in understanding the structural and optical properties of Carbon dots (CDs). The exceptional photoluminescence properties exhibited by CDs derived from natural products have paved the way for applications in tissue engineering, cancer treatment, bioimaging, sensing, drug delivery, photocatalysis, and promising remarkable advancements in these fields. In this review, we summarized the various synthesis methods, physical and optical properties, applications, challenges, future prospects of natural products-derived carbon dots etc. In this expanding sector, the difficulties and prospects for NCD-based materials research will also be explored.

177 Lu Radiolabelled AIE Dots for Multimodal Imaging Guided Photothermal/Radiopharmaceutical Tumor Therapy.

Aggregation-induced emission luminogens (AIEgens) in the second near-infrared region (NIR-II,1000-1700 nm) have shown tremendous potential as theragnostic probe for tumor multimodal diagnostic imaging and combined treatment owing to their programmable optical, structural and functional properties. Herein, we presented a radionuclide 177 Lu-labeled AIEgen, 177 Lu-2TT-oC6B dots, for NIR-II fluorescence and SPECT/CT imaging-guided tumor photothermal and radiopharmaceutical therapy. Intriguingly, 177 Lu-2TT-oC6B self-assembled into 10 nm dots, exhibited high NIR-II fluorescence quantum yield (QY, 1.34 %) and unprecedented photothermal conversion efficiency (PCE, 70.3 %) in vitro, furtherly performed extremely long blood circulation (T1/2 =52.4 h), persistent tumor accumulation and retention in tumor (NIR-II SNR=5.56; SPECT SNR=36.59) via intravenous administration in vivo. Furthermore, upon NIR light activation and 177 Lu irradiation, 177 Lu-2TT-oC6B demonstrated great application potential in synergistic photothermal/radiopharmaceutical tumor therapy.

Ce4+/Ce3+ as the switch of AIE-copper nanoclusters for highly selective detection of ascorbic acid in soft drinks.

An ultrasimple "turn-on" sensor for indirectly detecting ascorbic acid (AA) was prepared using N-acetyl-L-cysteine stabilized copper nanoclusters (NAC-CuNCs) via the AIE (aggregation-induced emission) effect controlled by Ce4+/Ce3+ redox reaction. This sensor fully utilizes the different properties of Ce4+ and Ce3+. Non-emissive NAC-CuNCs were synthesized by a facile reduction method. NAC-CuNCs easily aggregate in the presence of Ce3+ due to AIE, resulting in fluorescence enhancement. However, this phenomenon cannot be observed in the presence of Ce4+. Ce4+ possesses strong oxidizing ability and produces Ce3+ by reacting with AA via a redox reaction, followed by switching on the luminescence of NAC-CuNCs. Moreover, the fluorescence intensity (FI) of NAC-CuNCs increases with the concentration of AA in the range of 4-60 µM, with the limit of detection (LOD) as low as 0.26 µM. This probe with excellent sensitivity and selectivity was successfully used in the determination of AA in soft drinks.

Molecular Engineering of NIR-II/IIb Emitting AIEgen for Multimodal Imaging-Guided Photo-Immunotherapy.

In view of the great challenges related to the complexity and heterogeneity of tumors, efficient combination therapy is an ideal strategy for eliminating primary tumors and inhibiting distant tumors. A novel aggregation-induced emission (AIE) phototherapeutic agent called T-TBBTD is developed, which features a donor-acceptor-donor (D-A-D) structure, enhanced twisted molecule conformation, and prolonged second near-infrared window (NIR-II) emission. The multimodal imaging function of the molecule has significance for its treatment time window and excellent photothermal/photodynamic performance for multimode therapy. The precise molecular structure and versatility provide prospects for molecular therapy for anti-tumor applications. Fluorescence imaging in the NIR-II window offers advantages with enhanced spatial resolution, temporal resolution, and penetration depth. The prepared AIE@R837 NPs also have controllable performance for antitumor photo-immunotherapy. Following local photo-irradiation, AIE@R837 NPs generate abundant heat, and 1 O2 directly kills tumor cells, induces immunogenic cell death (ICD) as a photo-therapeutic effect, and releases R837, which enhances the synergistic effect of antigen presentation and contributes to the long-lasting protective antitumor immunity. A bilateral 4T1 tumor model revealed that this photo-immunotherapy can eliminate primary tumors. More importantly, it has a significant inhibitory effect on distant tumor growth. Therefore, this method can provide a new strategy for tumor therapy.

Facile Transformation from Rofecoxib to a New Near-Infrared Lipid Droplet Fluorescent Probe and Its Investigations on AIE Property, Solvatochromism and Mechanochromism.

Lipid-related cancers cause a large number of deaths worldwide. Therefore, development of highly efficient Lipid droplets (LDs) fluorescent imaging probes will be beneficial to our understanding of lipid-related cancers by allowing us to track the metabolic process of LDs. In this work, a LDs-specific NIR (λmax = 698 nm) probe, namely BY1, was rationally designed and synthesized via a one-step reaction by integrating triphenylamine (electron-donor group) unit into the structure of rofecoxib. This integration strategy enabled the target BY1 to form a strong Donor-Acceptor (D-A) system and endowed BY1 with obvious aggregation-induced emission (AIE) effect. Meanwhile, BY1 also showed observable solvent effect and reversible mechanochromatic luminescent property, which could be interpreted clearly via density functional theory (DFT) calculations, differential scanning calorimetry (DSC), powder X-ray diffraction (XPRD), and single crystal X-ray data analysis. More importantly, BY1 exhibited highly specific fluorescent imaging ability (Pearson's correlation = 0.97) towards lipid droplets in living HeLa cells with low cytotoxicity. These results demonstrated that BY1 is a new promising fluorescent probe for lipid droplets imaging, and it might be beneficial to facilitate biological research of lipid-related cancers.

TfR Aptamer Enhanced Blood-Brain Barrier Penetration of Biomimetic Nanocomplexes for Intracellular Transglutaminase 2 Imaging and Silencing in Glioma.

Engineering a versatile nanocomplex integrating effective penetration of the blood-brain barrier (BBB), accurate diagnosis, and boosting therapy has always been an intractable challenge in glioblastoma multiforme (GBM). Herein, biomimetic nanocomplexes (TMPsM) for single intracellular transglutaminase 2 (TG2)-triggered self-assembly imaging and RNAi therapy for GBM are subtly developed. To prove the concept, transferrin receptor (TfR) aptamer-modified brain metastatic tumor cell membrane is prepared as the shell for dual BBB targeting capability and prolonged blood retention time. Upon targeting entering into GBM, hollow MnO2 is decomposed to release KKGKGQQ-tetraphenylethene (Pep-TPE) and siRNA. Owing to TG2 dependence, the non-emissive Pep-TPE would be self-aggregated to induce the emission turn-on in GBM that contain overexpressed TG2. The resulting aggregation-induced emission fluorescence imaging with a high signal-to-noise ratio can achieve the precise localization of the tumor and dynamic detection of TG2 activity, thereby allowing the GBM accurate diagnosis. Notably, the TG2 can be silenced by the released siRNA to cause cell apoptosis and increase chemotherapeutic sensitivity, ultimately realizing excellent antitumor efficacy. In vitro and in vivo results demonstrate that the as-prepared TMPsM indeed possess superior BBB penetration, precise diagnosis, and effective therapy of GBM. The proposed strategy may pioneer a new path for the theranostics of brain tumors.

Molecular Design and Photothermal Application of Thienoisoindigo Dyes with Aggregation-Induced Emission.

Organic fluorescent dyes with aggregation-induced emission (AIE) property have an extensive application range, especially in the fields of imaging, labeling, and adjusting microprocesses in aggregated environments. In particular, the thienoisoindigo skeleton, which exhibits an outstanding electron-withdrawing capacity in optoelectronic materials, has been defined as a promising AIE candidate. For instance, by installing AIE blocks or other rotatable groups at two terminal sites, such as various arylamine groups, thienoisoindigo derivatives can be efficiently turned to be functional AIE structures. In this work, a thienoisoindigo derivative with AIE characteristics, namely, TII-TPE, was developed. This AIE system was expanded by linking typical AIE fragments, namely, tetraphenylethene, with the proposed thienoisoindigo derivative, which exhibited typical AIE fluorescence in the 600-850 nm range and maintained high photostability. Then, employing the reported derivative TII-TPA coating thienoisoindigo and triphenylamine as a contrast, aggregated TII-TPE and TII-TPA nanoparticles were prepared and demonstrated photothermal conversion efficiencies of 36.2 and 35.6%, respectively. Moreover, both nanoparticles were evaluated as photothermal therapeutic (PTT) agents in a tumor mouse model, which showed to significantly inhibit tumor growth after four treatment cycles in vivo. This work not only presents an enriched thienoisoindigo system but also provides a pattern for subsequent construction of functional AIE molecules.

Design and fabrication of chitosan-based AIE active micelles for bioimaging and intelligent delivery of paclitaxel.

In this study, cetyl 4-formylbenzoate alkyl and 4-(2-hydroxyethoxy) benzophenonesalicylaldazide modified biotinylated chitosan (CS-BT-HBS-CB) featured with aggregation-induced emission (AIE) characteristic, active tumor-targeting ability and pH-responsive drug release property was designed and synthesized. The polymer was fabricated by introducing hydrophobic segment, tumor targeting ligand, acid-sensitive bond and AIE fluorophore to the backbone of chitosan. Due to its amphiphilicity, the polymer could self-assemble into micelles and encapsulate paclitaxel (PTX) to form PTX-loaded CS-BT-HBS-CB micelles. The mean size of the micelles was 167 nm, which was beneficial to the EPR effect. Moreover, with the help of above functional groups, the micelles exhibited excellent AIE effect, triggered drug release behavior by acidic condition, selective internalization by MCF-7 cells and excellent cellular imaging capability. In vivo studies revealed that the PTX-loaded CS-BT-HBS-CB micelles could enhance the antitumor efficacy with low systemic toxicity. This micellar system would be a potential candidate for cancer therapy and bioimaging.

Prospects of NIR fluorescent nanosensors for green detection of SARS-CoV-2.

The pandemic of the novel coronavirus disease 2019 (COVID-19) is continuously causing hazards for the world. Effective detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can relieve the impact, but various toxic chemicals are also released into the environment. Fluorescence sensors offer a facile analytical strategy. During fluorescence sensing, biological samples such as tissues and body fluids have autofluorescence, giving false-positive/negative results because of the interferences. Fluorescence near-infrared (NIR) nanosensors can be designed from low-toxic materials with insignificant background signals. Although this research is still in its infancy, further developments in this field have the potential for sustainable detection of SARS-CoV-2. Herein, we summarize the reported NIR fluorescent nanosensors with the potential to detect SARS-CoV-2. The green synthesis of NIR fluorescent nanomaterials, environmentally compatible sensing strategies, and possible methods to reduce the testing frequencies are discussed. Further optimization strategies for developing NIR fluorescent nanosensors to facilitate greener diagnostics of SARS-CoV-2 for pandemic control are proposed.

A multifunctional AIE gold cluster-based theranostic system: tumor-targeted imaging and Fenton reaction-assisted enhanced radiotherapy.

BACKGROUND: As cancer is one of the main leading causes of mortality, a series of monotherapies such as chemotherapy, gene therapy and radiotherapy have been developed to overcome this thorny problem. However, a single treatment approach could not achieve satisfactory effect in many experimental explorations. RESULTS: In this study, we report the fabrication of cyclic RGD peptide (cRGD) modified Au4-iron oxide nanoparticle (Au4-IO NP-cRGD) based on aggregation-induced emission (AIE) as a multifunctional theranostic system. Besides Au4 cluster-based fluorescence imaging and enhanced radiotherapy, iron oxide (IO) nanocluster could realize magnetic resonance (MR) imaging and Fenton reaction-based chemotherapy. Abundant toxic reactive oxygen species generated from X-ray irradiation and in situ tumor-specific Fenton reaction under acidic microenvironment leads to the apoptotic and necrotic death of cancer cells. In vivo studies demonstrated good biocompatibility of Au4-IO NP-cRGD and a high tumor suppression rate of 81.1% in the synergistic therapy group. CONCLUSIONS: The successful dual-modal imaging and combined tumor therapy demonstrated AIE as a promising strategy for constructing multifunctional cancer theranostic platform.

AIE materials for nucleus imaging.

Emergence of a captivating phenomenon aggregation induced emission (AIE) in the early years of 21st century attracted worldwide researchers. In the last two decades various novel AIE active biocompatible small molecules, macromolecules and polymers have been developed for diverse biomedical applications. Imaging of specific organelle such as mitochondria, ribosomes, nuclei and many others play important in the controlling and successful treatment of various diseases. Conventional luminescent probe molecules used in the imaging at cellular or subcellular level exhibit very weak emission on dispersion or on aggregation in aqueous media. AIE luminogens development is indispensable to overcome the notorious aggregation-caused quenching (ACQ) issue inherited by conventional fluorophores. In the present chapter we mostly highlighted over one decade development of various AIE active luminogens utilized for imaging of cell nucleus, nucleon and nucleic acids. The development of those AIE luminogens exhibits promising results in the early diagnosis of cancer diseases.