Thiophene assisted cellular uptake enhancement for highly efficient NIR-II cancer phototheranostics.

We designed two series of NIR-II PTAs with D-A or D-A-D structures, in which the introduction of thiophene promotes a bathochromic shift of emission into the NIR-II region, helps to improve the cellular uptake of the PTAs and facilitates NIR-II imaging-guided PDT/PTT cancer phototherapy.

Sulfur oxidation states manipulate excited state electronic configurations for constructing highly efficient organic type I photosensitizers.

The multiple relaxation processes of excited states are a bridge connecting molecular structures and properties, providing enormous application potential for organic luminogens. However, a systematic understanding and manipulation of the relationship between the molecular structure, excited state relaxation processes, and properties of organic luminogens is still lacking. Herein, we report a strategy for manipulating excited state electronic configurations through the regulation of the sulfur oxidation state to construct eminent organic type I PSs. Combined with the experimental results and theoretical calculations, we have successfully revealed the decisive role of high sulfur oxidation states in promoting ROS production capacity. Impressively, a higher sulfur oxidation state can reduce the singlet-triplet energy gap (ΔE ST), increase the matching degree of transition configurations, promote the changes of the excited state electronic configurations, and boost the effective ISC proportion by enhancing intramolecular interactions. Therefore, DBTS2O with the highest sulfur oxidation state exhibits the strongest type I ROS generation ability. Additionally, guided by our strategy, a water-soluble PS (2OA) is designed and synthesized, showing selective imaging capacity and photokilling ability against Gram-positive bacteria. This study broadens the horizons for both molecular design and mechanism study of high-performance organic type I PSs.

White-light activatable organic NIR-II luminescence nanomaterials for imaging-guided surgery.

While second near-infrared (NIR-II) fluorescence imaging is a promising tool for real-time surveillance of surgical operations, the previously reported organic NIR-II luminescent materials for in vivo imaging are predominantly activated by expensive lasers or X-ray with high power and poor illumination homogeneity, which significantly limits their clinical applications. Here we report a white-light activatable NIR-II organic imaging agent by taking advantages of the strong intramolecular/intermolecular D-A interactions of conjugated Y6CT molecules in nanoparticles (Y6CT-NPs), with the brightness of as high as 13315.1, which is over two times that of the brightest laser-activated NIR-II organic contrast agents reported thus far. Upon white-light activation, Y6CT-NPs can achieve not only in vivo imaging of hepatic ischemia reperfusion, but also real-time monitoring of kidney transplantation surgery. During the surgery, identification of the renal vasculature, post-reconstruction assessment of renal allograft vascular integrity, and blood supply analysis of the ureter can be vividly depicted by using Y6CT-NPs with high signal-to-noise ratios upon clinical laparoscopic LED white-light activation. Our work provides efficient molecular design guidelines towards white-light activatable imaging agent and highlights an opportunity for precision imaging theranostics.

Recent advances of aggregation-induced emission luminogens for point-of-care biosensing systems.

The rapid and sensitive detection of chemical compounds in body fluids and tissues is important for diagnosis of diseases and assessment of the effectiveness of treatment programs. Point-of-care (POC) sensors based on fluorescence signals have been widely used in the rapid detection of various infectious diseases. However, the aggregation-caused quenching phenomenon of conventional fluorescent probes limits the sensitivity and accuracy of fluorescent POC sensors. In this review, we first focus on aggregation-induced emission (AIE)-based POC detection for early diagnosis of diseases and then describe how to use mechanisms of AIE to improve the sensitivity of POC testing. This review gives a summary of the design mechanisms of AIE probes in AIE-based biosensors. Subsequently, it summarizes the design strategies of AIE-based POC sensors in the detection of ions, small molecules, nucleic acids, proteins, and whole entity (cells, bacteria, viruses, and exosomes), placing an emphasis on signal amplification. Finally, it gives an overview of AIE-based POC biosensors, including probes, instruments, and applications. We hope that this review will provide valuable guidance for further expanding the application of AIE luminogens in POC biosensors.

Anion-π+ AIEgens for Fluorescence Imaging and Photodynamic Therapy.

Fluorescence imaging-guided photodynamic therapy (PDT) has attracted extensive attention due to its potential of real-time monitoring the lesion locations and visualizing the treatment process with high sensitivity and resolution. Aggregation-induced emission luminogens (AIEgens) show enhanced fluorescence and reactive oxygen species (ROS) generation after cellular uptake, giving them significant advantages in bioimaging and PDT applications. However, most AIEgens are unfavorable for the application in organisms due to their severe hydrophobicity. Anion-π+ type AIEgens carry intrinsic charges that can effectively alleviate their hydrophobicity and improve their binding capability to cells, which is expected to enhance the bioimaging quality and PDT performance. This concept summarizes the applications of anion-π+ type AIEgens in fluorescence imaging, fluorescence imaging-guided photodynamic anticancer and antimicrobial therapy in recent years, hoping to provide some new ideas for the construction of robust photosensitizers. Finally, the current problems and future challenges of anion-π+ AIEgens are discussed.

Effect of Ropivacaine Intercostal Nerve Block Combined with Patient Controlled Intravenous Analgesia on Postoperative Analgesia after Breast Augmentation.

BACKGROUNDS: To observe the effect of ropivacaine intercostal nerve block combined with PCIA as early postoperative analgesia following breast augmentation surgery with prosthesis (axillary approach) METHODS: A total of 80 women with breast augmentation surgery were selected in the plastic surgery department of Chongqing Huamei Plastic Surgery Hospital from December 2021 to May 2022. They were equally randomized into control group and observation group, with 40 cases in each one. Before placing the prosthesis, the control group was given 0.9% normal saline for intercostal nerve block; the observation group was given 0.75% ropivacaine + 1‰ adrenaline for intercostal nerve block. Patient controlled intravenous analgesia (PCIA) was used after operation. Observation indexes the visual analog scale (VAS) of resting and motor state at 4 h, 24 h, 48 h and 72 h after operation and the adverse reactions. RESULTS: The VAS scores of patients at rest and exercise and adverse reactions in the observation group were lower than those in the control group (P<0.05). CONCLUSION: Ropivacaine intercostal nerve block combined with PCIA can effectively alleviate the pain after breast augmentation with pectoralis major prosthesis through axillary incision, help patients more comfortably through the perioperative period, accelerate postoperative recovery, reduce the dosage of systemic opioids and effectively reduce side effects. LEVEL OF EVIDENCE II: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

A Highly Water-Soluble Aggregation-Induced Emission Luminogen with Anion-π+ Interactions for Targeted NIR Imaging of Cancer Cells and Type†I Photodynamic Therapy.

The low oxygen dependence of type I photosensitizers (PSs) has made them a popular choice for treating solid tumors. However, the drawbacks of poor water solubility, short emission wavelength, poor stability, and inability to distinguish cancer cells from normal cells limit the application of most type I PSs in clinical therapy. Thereby, developing novel type I PSs for overcoming these problems is an urgent but challenging task. Herein, by utilizing the distinctive structural characteristics of anion-π+ interactions, a highly water-soluble type I PS (DPBC-Br) with aggregation-induced emission (AIE) characteristic and near-infrared (NIR) emission is fabricated for the first time. DPBC-Br displays remarkable water solubility (7.3 mM) and outstanding photobleaching resistance, enabling efficient and precise differentiation between tumor cells and normal cells in a wash-free and long-term tracking manner via NIR-I imaging. Additionally, the superior type I reactive oxygen species (ROS) produced by DPBC-Br provide both specific killing of cancer cells in vitro and inhibition of tumor growth in vivo, with negligible systemic toxicity. This study rationally constructs a highly water-soluble type I PS, which has higher reliability and controllability compared with conventional nanoparticle formulating procedures, offering great potential for clinical cancer treatment.

Oxidization enhances type I ROS generation of AIE-active zwitterionic photosensitizers for photodynamic killing of drug-resistant bacteria.

Type I photosensitizers (PSs) with an aggregation-induced emission (AIE) feature have received sustained attention for their excellent theranostic performance in the treatment of clinical diseases. However, the development of AIE-active type I PSs with strong reactive oxygen species (ROS) production capacity remains a challenge due to the lack of in-depth theoretical studies on the aggregate behavior of PSs and rational design strategies. Herein, we proposed a facile oxidization strategy to enhance the ROS generation efficiency of AIE-active type I PSs. Two AIE luminogens, MPD and its oxidized product MPD-O were synthesized. Compared with MPD, the zwitterionic MPD-O showed higher ROS generation efficiency. The introduction of electron-withdrawing oxygen atoms results in the formation of intermolecular hydrogen bonds in the molecular stacking of MPD-O, which endowed MPD-O with more tightly packed arrangement in the aggregate state. Theoretical calculations demonstrated that more accessible intersystem crossing (ISC) channels and larger spin-orbit coupling (SOC) constants provide further explanation for the superior ROS generation efficiency of MPD-O, which evidenced the effectiveness of enhancing the ROS production ability by the oxidization strategy. Moreover, DAPD-O, a cationic derivative of MPD-O, was further synthesized to improve the antibacterial activity of MPD-O, showing excellent photodynamic antibacterial performance against methicillin-resistant S. aureus both in vitro and in vivo. This work elucidates the mechanism of the oxidization strategy for enhancing the ROS production ability of PSs and offers a new guideline for the exploitation of AIE-active type I PSs.

In Vivo Fluorescence Imaging-Guided Development of Near-Infrared AIEgens.

In vivo fluorescence imaging has received extensive attention due to its distinguished advantages of excellent biosafety, high sensitivity, dual temporal-spatial resolution, real-time monitoring ability, and non-invasiveness. Aggregation-induced emission luminogens (AIEgens) with near-infrared (NIR) absorption and emission wavelengths are ideal candidate for in vivo fluorescence imaging for their large Stokes shift, high brightness and superior photostability. NIR emissive AIEgens provide deep tissue penetration depth as well as low interference from tissue autofluorescence. Here in this review, we summarize the molecular engineering strategies for constructing NIR AIEgens with high performances, including extending π-conjugation system and strengthen donor (D)-acceptor (A) interactions. Then the encapsulation strategies for increasing water solubility and biocompatibility of these NIR AIEgens are highlighted. Finally, the challenges and prospect of fabricating NIR AIEgens for in vivo fluorescence imaging are also discussed. We hope this review would provide some guidelines for further exploration of new NIR AIEgens.

Anion-π Type Aggregation-Induced Emission Luminogens.

As a type of important non-covalent interactions that can efficiently prohibit π-π interaction to avoid quenching of luminescence, anion-π interactions are receiving growing attention for the fabrication of aggregation-induced emission luminogens (AIEgens) since 2017. The obtained anion-π type AIEgens can be applied in the fields of wash-free bioimaging and long-term tracking of subcellular organelle, photodynamic anti-cancer and anti-bacterial therapy due to their good water solubility, superior photostability and excellent reactive oxygen species generation ability. Moreover, anion-π type AIEgens were also further constructed for room temperature phosphorescence by taking advantages of the heavy-atom participated anion-π interactions. This concept article provides a brief summary of this field, mainly focusing on the design strategy, photophysical properties and applications of anion-π type AIEgens.

Fluorination Enhances NIR-II Emission and Photothermal Conversion Efficiency of Phototheranostic Agents for Imaging-Guided Cancer Therapy.

Phototheranostics with second near-infrared (NIR-II) imaging and photothermal effect have become a burgeoning biotechnology for tumor diagnosis and precise treatment. As important parameters of phototheranostic agents (PTAs), fluorescence quantum yield (QY) and photothermal conversion efficiency (PCE) are usually considered as a pair of contradictions that is difficult to be simultaneously enhanced. Herein, a fluorination strategy for designing A-D-A type PTAs with synchronously improved QY and PCE is proposed. Experimental results show that the molar extinction coefficient (ε), NIR-II QY, and PCE of all fluorinated PTAs nanoparticles (NPs) are definitely improved compared with the chlorinated counterparts. Theoretical calculation results demonstrate that fluorination can maximize the electrostatic potential difference by virtue of the high electronegativity of fluorine, which may increase intra/intermolecular D-A interactions, tighten molecule packing, and further promote the increase of ε, ultimately leading to simultaneously enhanced QY and PCE. In these PTA NPs, FY6-NPs display NIR-II emission extended to 1400 nm with the highest NIR-II QY (4.2%) and PCE (80%). These features make FY6-NPs perform well in high-resolution imaging of vasculature and NIR-II imaging-guided photothermal therapy (PTT) of tumors. This study develops a valuable guideline for constructing NIR-II organic PTAs with high performance.

A Facile Structural Isomerization-Induced 3D Spatial D-A Interlocked Network for Achieving NIR-II Phototheranostic Agents.

The performances of second near-infrared (NIR-II) organic phototheranostic agents (OPTAs) depend on both molecular structure and molecular packing when used as nanoparticles (NPs). Herein, we proposed a facile structural isomerization-induced 3D spatial donor (D)-acceptor (A) interlocked network for achieving NIR-II OPTAs. Two isomers, 4MNVDPP and 6MNVDPP were synthesized and formulated into NPs. 6MNVDPP, which has a larger electrostatic potential difference, exhibits a compact 3D spatial D-A interlocked network in the crystal form, while 4MNVDPP forms 2D D-D type J-aggregates. Thus, 6MNVDPP NPs show red-shifted NIR absorption and larger molar extinction coefficient than 4MNVDPP NPs. Thanks to the typical NIR-II emission, superior photothermal-stability, high photothermal conversion efficiency (89 %) and reactive oxygen species production capacity, 6MNVDPP NPs exhibit outstanding NIR-II tiny capillary vasculature/tumor imaging ability and synergistic photothermal/photodynamic anti-cancer effect in vivo.

Dipole-Dipole and Anion-π+ Interaction Manipulation Synergistically Enhance Intrinsic Antibacterial Activities of AIEgens.

Pathogenic bacteria infections, especially multidrug resistant bacteria infections have aroused worldwide attention due to their severe threats to human beings. Thus, the development of highly effective antibacterial reagents is very important. However, the design of antimicrobials is still quite challenging for the lack of a universal design strategy. Here, a synergistic manipulation strategy of dipole-dipole and anion-π+ interaction is proposed for constructing highly efficient antimicrobials with aggregation-induced emission (AIE) feature. Firstly, four anion-π+ -type AIE luminogens were designed and synthesized. Due to the electron-donating and hydrophilic characteristic of methoxy groups, 3MOTPO containing three methoxy groups showed the largest dipole moment (5.06 Debye) and dual anion-π+ interactions in the solid state. Driven by both dipole-dipole and anion-π+ interactions, 3MOTPO showed the strongest bacterial binding ability and the best antibacterial activities (MIC90 =3.76 µM). The work offers a deep insight into the rational design of highly efficient antimicrobials for luminescence-guided antibacterial study.

A Fast-Response AIE-Active Ratiometric Fluorescent Probe for the Detection of Carboxylesterase.

Hepatocellular carcinoma (HCC) is associated with a high mortality rate worldwide. The therapeutic outcomes can be significantly improved if diagnosis and treatment are initiated earlier in the disease process. Recently, the carboxylesterase (CaE) activity/level in human plasma was reported to be a novel serological biomarker candidate for HCC. In this article, we fabricated a new fluorescent probe with AIE characteristics for the rapid detection of CaE with a more reliable ratiometric response mode. The TCFISE probe showed high sensitivity (LOD: 93.0 µU/mL) and selectivity toward CaE. Furthermore, the good pH stability, superior resistance against photobleaching, and low cytotoxicity highlight the high potential of the TCFISE probe for application in the monitoring of CaE activity in complex biological samples and in live cells, tissues, and animals.

Acceptor Planarization and Donor Rotation: A Facile Strategy for Realizing Synergistic Cancer Phototherapy via Type I PDT and PTT.

Tumor hypoxia seriously impairs the therapeutic outcomes of type II photodynamic therapy (PDT), which is highly dependent upon tissue oxygen concentration. Herein, a facile strategy of acceptor planarization and donor rotation is proposed to design type I photosensitizers (PSs) and photothermal reagents. Acceptor planarization can not only enforce intramolecular charge transfer to redshift NIR absorption but also transfer the type of PSs from type II to type I photochemical pathways. Donor rotation optimizes photothermal conversion efficiency (PCE). Accordingly, three 3,6-divinyl-substituted diketopyrrolopyrrole (DPP) derivatives, 2TPAVDPP, TPATPEVDPP, and 2TPEVDPP, with different number of rotors were prepared. Experimental results showed that three compounds were excellent type I PSs, and the corresponding 2TPEVDPP nanoparticles (NPs) with the most rotors possessed the highest PCE. The photophysical properties of 2TPEVDPP NPs are particularly suitable for in vivo NIR fluorescence imaging-guided synergistic PDT/PTT therapy. The proposed strategy is helpful for exploiting type I phototherapeutic reagents with high efficacy for synergistic PDT and PTT.

Lysosome-Targeting Red-Emitting Aggregation-Induced Emission Probe with Large Stokes Shift for Light-Up in Situ Visualization of ß-N-Acetylhexosaminidase.

Lysosomal ß-N-acetylhexosaminidase (Hex) has been reported to possess unique physiological performances. Detection and visualization of Hex in lysosome will be favorable to reveal the basis of its functions. However, Hex-specific fluorescent probes are rarely reported. In this study, we reported the first lysosome-targeting Hex-lighting-up aggregation-induced emission (AIE)-active fluorescent probe (GlcNAc-TPE) with remarkably large Stokes shift and high sensitivity and selectivity. GlcNAc-TPE can selectively locate in lysosome and visualize endogenous Hex in live HCT116 cells and in live mice with high stability and good biocompatibility, providing a useful AIE probe for real-time visualization of Hex in live samples.

New switch on fluorescent probe with AIE characteristics for selective and reversible detection of mercury ion in aqueous solution.

A new tetraphenylethylene derivative based fluorescenct probe (probe 2) was synthesized in a simple two-step process for selectively switch on and reversible detection of Hg2+ in aqueous solution based on aggregation-induced emission phenomenon. Probe 2 exhibited weak emission in aqueous solution due to the fast non-radiative decay of the excited singlet state facilitated by the free rotation of four phenyl rotors. While after coordination with Hg2+, the Hg2+-promoted aggregation formation will occur and restrict the intramolecular rotation, which blocks the non-radiative pathways and opens up the emission channel, resulting in the switch on response of probe 2 toward Hg2+. Probe 2 exhibited high sensitivity and good selectivity toward Hg2+ with a detection limit of 45.4 nM. Moreover, the detection can be reversible by subsequent addition of S2- into the detection system, which may be applied in the removal of toxic Hg2+ from water. Elsevier B.V. All rights reserved.

An Easily Available Ratiometric Reaction-Based AIE Probe for Carbon Monoxide Light-up Imaging.

Carbon monoxide (CO) is a significant gasotransmitter that naturally modulates inflammatory responses. Visualization of CO in situ would help to reveal its physiological/pathological functions. Unfortunately, most existing CO fluorescent probes show aggregation-caused quenching (ACQ) properties. Herein, we report the reaction-based fluorescent probe (BTCV-CO) with aggregation-induced emission (AIE) characteristics for CO detection and imaging. This ratiometric AIE probe showed excellent stability, high sensitivity (detection limit of 30.8 nM), and superior selectivity. More importantly, this CO-responsive AIE probe could be facilely designed and easily obtained by two-step synthesis with high yield, providing an easy-to-handle AIE toolbox for real-time visualization of CO in a living system.

Selectively light-up hydrogen peroxide in hypoxic cancer cells with a novel fluorescent probe.

A novel fluorescent turn-on probe (HCyHP) was developed in a simple two-step synthesis for monitoring of exogenous and endogenous H2O2 levels in biological samples and hypoxic cancer diagnosis.

A fast responsive, highly selective and light-up fluorescent probe for the two-photon imaging of carboxylesterase in living cells.

A fast responsive and two photon fluorescent probe (HCyNAc) for carboxylesterase (CaE) has been designed based on the D-π-A structure of hemicyanine and naphthalene derivatives. After enzymatic reaction, HCyNAc enabled light-up fluorescence assay of CaE over other biologically-relevant species and enzymes, including ROS. Two-photon imaging of endogenous CaE was confirmed in HeLa cells using HCyNAc under 800 nm NIR excitation.