Precise Two‐Photon Photodynamic Therapy using an Efficient Photosensitizer with Aggregation‐Induced Emission Characteristics

Two‐photon photodynamic therapy (PDT) is able to offer precise 3D manipulation of treatment volumes, providing a target level that is unattainable with current therapeutic techniques. The advancement of this technique is greatly hampered by the availability of photosensitizers with large two‐photon absorption (TPA) cross section, high reactive‐oxygen‐species (ROS) generation efficiency, and bright two‐photon fluorescence. Here, an effective photosensitizer with aggregation‐induced emission (AIE) characteristics is synthesized, characterized, and encapsulated into an amphiphilic block copolymer to form organic dots for two‐photon PDT applications. The AIE dots possess large TPA cross section, high ROS generation efficiency, and excellent photostability and biocompatibility, which overcomes the limitations of many conventional two‐photon photosensitizers. Outstanding therapeutic performance of the AIE dots in two‐photon PDT is demonstrated using in vitro cancer cell ablation and in vivo brain‐blood‐vessel closure as examples. This shows therapy precision up to 5 µm under two‐photon excitation.     

Highly Efficient Photosensitizers with Far‐Red/Near‐Infrared Aggregation‐Induced Emission for In Vitro and In Vivo Cancer Theranostics

Fluorescence‐imaging‐guided photodynamic therapy has emerged as a promising protocol for cancer theranostics. However, facile preparation of such a theranostic material for simultaneously achieving bright emission with long wavelength, high‐performance reactive oxygen species (ROS) generation, and good targeting‐specificity of cancer cells, is highly desirable but remains challenging. In this study, a novel type of far‐red/near‐infrared‐emissive fluorescent molecules with aggregation‐induced emission (AIE) characteristics is synthesized through a few steps reaction. These AIE luminogens (AIEgens) possess simple structures, excellent photostabilities, large Stokes shifts, bright emission, and good biocompatibilities. Meanwhile, their ROS generation is extremely efficient with up to 90.7% of ROS quantum yield, which is far superior to that of some popularly used photosensitizers. Importantly, these AIEgens are able to selectively target and ablate cancer cells over normal cells without the aid of any extra targeting ligands. Rather than using laser light, one of the presented AIEgens (MeTTPy) shows a remarkable tumor‐targeting photodynamic therapeutic effect by using an ultralow‐power lamp light (18 mW cm^?2). This study thus not only extends the applications scope of AIEgens, but also offers useful insights into designing a new generation of cancer theranostics.     

Corannulene‐Incorporated AIE Nanodots with Highly Suppressed Nonradiative Decay for Boosted Cancer Phototheranostics In Vivo

Fluorescent nanoparticles (NPs) based on luminogens with aggregation‐induced emission characteristic (AIEgens), namely AIE dots, have received wide attention because of their antiquenching attitude in emission and reactive oxygen species (ROS) generation when aggregated. However, few reports are available on how to control and optimize their fluorescence and ROS generation ability. Herein, it is reported that enhancing the intraparticle confined microenvironment is an effective approach to advanced AIE dots, permitting boosted cancer phototheranostics in vivo. Formulation of a “rotor‐rich” and inherently charged near‐infrared (NIR) AIEgen with 1,2‐distearoyl‐sn‐glycero‐3‐phosphoethanolamine‐N‐[methoxy(polyethylene glycol)‐2000] and corannulene‐decorated PEG affords DSPE‐AIE dots and Cor‐AIE dots, respectively. Compared to DSPE‐AIE dots, Cor‐AIE dots show 4.0‐fold amplified fluorescence quantum yield and 5.4‐fold enhanced ROS production, because corannulene provides intraparticle rigidity and strong interactions with the AIEgen to restrict the intramolecular rotation of AIEgen to strongly suppress the nonradiative decay and significantly facilitate the fluorescence pathway and intersystem crossing. Thus, it tremendously promotes phototheranostic efficacies in terms of NIR image‐guided cancer surgery and photodynamic therapy using a peritoneal carcinomatosis‐bearing mouse model. Collectively, it not only provides a novel strategy to advanced AIE dots for cancer phototheranostics, but also brings new insights into the design of superior fluorescent NPs for biomedical applications.     

An All-Round Athlete on the Track of Phototheranostics: Subtly Regulating the Balance between Radiative and Nonradiative Decays for Multimodal Imaging-Guided Synergistic Therapy

Aiming to achieve versatile phototheranostics with the integrated functionalities of multiple diagnostic imaging and synergistic therapy, the optimum use of dissipated energy through both radiative and nonradiative pathways is definitely appealing, yet a significantly challenging task. To the best of the knowledge, there have been no previous reports on a single molecular species effective at affording all phototheranostic modalities including fluorescence imaging (FLI), photoacoustic imaging (PAI), photothermal imaging (PTI), photodynamic therapy (PDT), and photothermal therapy (PTT). Herein, a simple and highly powerful one-for-all phototheranostics based on aggregation-induced emission (AIE)-active fluorophores is tactfully designed and constructed. Thanks to its strong electron donor–acceptor interaction and finely modulated intramolecular motion, the AIE fluorophore-based nanoparticles simultaneously exhibit bright near-infrared II (NIR-II) fluorescence emission, efficient reactive oxygen species generation, and high photothermal conversion efficiency upon NIR irradiation, indicating the actualization of a balance between radiative and nonradiative energy dissipations. Furthermore, the unprecedented performance on NIR-II FLI-PAI-PTI trimodal-imaging-guided PDT–PTT synergistic therapy is demonstrated by the precise tumor diagnosis and complete tumor elimination outcomes. This study thus brings a new insight into the development of superior versatile phototheranostics for practical cancer theranostics.     

Multiscale Humidity Visualization by Environmentally Sensitive Fluorescent Molecular Rotors

Building humidity sensors possessing the features of diverse‐configuration compatibility, and capability of measurement of spatial and temporal humidity gradients is of great interest for highly integrated electronics and wearable monitoring systems. Herein, a visual sensing approach based on fluorescent imaging is presented, by assembling aggregation‐induced‐emission (AIE)‐active molecular rotors into a moisture‐captured network; the resulting AIE humidity sensors are compatible with diverse applications, having tunable geometries and desirable architectures. The invisible information of relative humidity (RH) is transformed into different fluorescence colors that enable direct observation by the naked eyes based on the twisted intramolecular charge‐transfer effect of the AIE‐active molecular rotors. The resulting AIE humidity sensors show excellent performance in terms of good sensitivity, precise quantitative measurement, high spatial–temporal resolution, and fast response/recovery time. Their multiscale applications, such as regional environmental RH detection, internal humidity mapping, and sensitive human‐body humidity sensing are demonstrated. The proposed humidity visualization strategy may provide a new insight to develop humidity sensors for various applications.     

具有自组装纳米结构的AIE光敏剂用于增强光动力治疗（英文）

基于具有聚集诱导发光(AIE)性质的2,3-双(4’-(二苯基)-[1,1’-联苯]-4-基]富甲腈(BDBF)分子,制备了三种纳米结构并用于图像引导光动力学治疗(PDT).普兰尼克F127可包封BDBF形成常见的球形纳米粒子(F127@BDBF NPs),该纳米粒子可发射红色荧光,荧光量子效率(FQY)为9.8%.此外, BDBF也可在水中自组装成纳米棒(BDBF NRs).与F127@BDBF NPs相比, BDBF NRs呈现出较强的橙色荧光,具有较高的荧光量子产率(23.3%),以及基本相同的单线态氧(1O2)产生能力.利用F127对BDBF NRs进行进一步修饰可得到BDBF@F127 NRs,该纳米粒子仍然保持了棒状形貌和较好的1O2产生能力.同时,与溶解态的BDBF相比,三种纳米结构的单线态氧产生效率增强.这些纳米结构在水溶液和生理条件下具有良好的稳定性.细胞的光毒性实验表明,三种纳米结构均能有效抑制肿瘤细胞增殖.因此,通过简单的自组装方法制备高荧光量子效率和较强单线态氧产生能力的纳米结构可作为一种有效的途径来增强光动力.     

A Single Molecule Drug Targeting Photosensitizer for Enhanced Breast Cancer Photothermal Therapy

Targeting is one of the most important strategies for enhancing the efficacy of cancer photothermal therapy (PTT) and reducing damage to surrounding normal tissues. Compared with the traditional targeting approaches, the active targeting of breast cancer cells in PTT using chemotherapeutic drugs, such as tamoxifen (TAM), in combination with single‐molecule photothermal photosensitizers has superior selectivity and therapeutic effects. However, single‐molecule drug‐targeting photosensitizers for improved PTT efficacy are not widely reported. Accordingly, herein, a near‐infrared induced small‐molecule photothermal photosensitizer (CyT) is developed that actively targets the estrogen receptors (ERs) of breast cancer cells as well as targets mitochondria by structure‐inherent targeting. Cell uptake and cytotoxicity studies using different types of cells show that CyT enhances the efficiency of TAM‐based PTT by targeting ER‐overexpressing breast cancer cells and selectively killing them. In vivo experiments demonstrate that CyT can be used as a photothermal agent for fluorescence imaging‐guided PTT. More importantly, the intravenous injection of CyT results in better targeting and efficiency of tumor inhibition compared with that achieved with the TAM‐free control molecule Cy. Thus, the study presents an excellent small‐molecule photothermal agent for breast cancer therapy with potential clinical application prospects.     

The Nanoassembly of an Intrinsically Cytotoxic Near‐Infrared Dye for Multifunctionally Synergistic Theranostics

The combination of diagnostic and therapeutic functions in a single theranostic nanoagent generally requires the integration of multi‐ingredients. Herein, a cytotoxic near‐infrared (NIR) dye (IR‐797) and its nanoassembly are reported for multifunctional cancer theranostics. The hydrophobic IR‐797 molecules are self‐assembled into nanoparticles, which are further modified with an amphiphilic polymer (C18PMH‐PEG5000) on the surface. The prepared PEG‐IR‐797 nanoparticles (PEG‐IR‐797 NPs) possess inherent cytotoxicity from the IR‐797 dye and work as a chemotherapeutic drug which induces apoptosis of cancer cells. The IR‐797 NPs are found to have an ultrahigh mass extinction coefficient (444.3 L g^?1 cm^?1 at 797 nm and 385.9 L g^?1 cm^?1 at 808 nm) beyond all reported organic nanomaterials (<40 L g^?1 cm^?1) for superior photothermal therapy (PTT). In addition, IR‐797 shows some aggregation‐induced‐emission (AIE) properties. Combining the merits of good NIR absorption, high photothermal energy conversion efficiency, and AIE, makes the PEG‐IR‐797 NPs useful for multimodal NIR AIE fluorescence, photoacoustic, and thermal imaging‐guided therapy. The research exhibits the possibility of using a single ingredient and entity to perform multimodal NIR fluorescence, photoacoustic, and thermal imaging‐guided chemo‐/photothermal combination therapy, which may trigger wide interest from the fields of nanomedicine and medicinal chemistry to explore multifunctional theranostic organic molecules.     

A Highly Efficient and Photostable Photosensitizer with Near‐Infrared Aggregation‐Induced Emission for Image‐Guided Photodynamic Anticancer Therapy

Photodynamic therapy (PDT), which relies on photosensitizers (PS) and light to generate reactive oxygen species to kill cancer cells or bacteria, has attracted much attention in recent years. PSs with both bright emission and efficient singlet oxygen generation have also been used for image‐guided PDT. However, simultaneously achieving effective ¹O₂ generation, long wavelength absorption, and stable near‐infrared (NIR) emission with low dark toxicity in a single PS remains challenging. In addition, it is well known that when traditional PSs are made into nanoparticles, they encounter quenched fluorescence and reduced ¹O₂ production. In this contribution, these challenging issues have been successfully addressed through designing the first photostable photosensitizer with aggregation‐induced NIR emission and very effective ¹O₂ generation in aggregate state. The yielded nanoparticles show very effective ¹O₂ generation, bright NIR fluorescence centered at 820 nm, excellent photostability, good biocompatibility, and negligible dark in vivo toxicity. Both in vitro and in vivo experiments prove that the nanoparticles are excellent candidates for image‐guided photodynamic anticancer therapy.     

2D‐Black‐Phosphorus‐Reinforced 3D‐Printed Scaffolds:A Stepwise Countermeasure for Osteosarcoma

With the ever‐deeper understanding of nano–bio interactions and the development of fabrication methodologies of nanomaterials, various therapeutic platforms based on nanomaterials have been developed for next‐generation oncological applications, such as osteosarcoma therapy. In this work, a black phosphorus (BP) reinforced 3D‐printed scaffold is designed and prepared to provide a feasible countermeasure for the efficient localized treatment of osteosarcoma. The in situ phosphorus‐driven, calcium‐extracted biomineralization of the intra‐scaffold BP nanosheets enables both photothermal ablation of osteosarcoma and the subsequent material‐guided bone regeneration in physiological microenvironment, and in the meantime endows the scaffolds with unique physicochemical properties favoring the whole stepwise therapeutic process. Additionally, a corrugated structure analogous to Haversian canals is found on newborn cranial bone tissue of Sprague–Dawley rats, which may provide much inspiration for the future research of bone‐tissue engineering.     

Stereotactic Photodynamic Therapy Using a Two‐Photon AIE Photosensitizer

Two‐photon photodynamic therapy (TP‐PDT) is emerging as a powerful strategy for stereotactic targeting of diseased areas, but ideal photosensitizers (PSs) are currently lacking. This work reports a smart PS with aggregation‐induced emission (AIE) feature, namely DPASP, for TP‐PDT with excellent performances. DPASP exhibits high affinity to mitochondria, superior photostability, large two‐photon absorption cross section as well as efficient reactive oxygen species generation, enabling it to achieve photosensitization both in vitro and in vivo under two‐photon excitation. Moreover, its capability of stereotactic ablation of targeted cells with high‐precision is also successfully demonstrated. All these merits make DPASP a promising TP‐PDT candidate for accurate ablation of abnormal tissues with minimal damages to surrounding areas in the treatment of various diseases.     

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 ¹O₂ 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.     

Nd掺杂硅酸钙及其复合电纺丝膜的制备及性能研究

同时具有光热效应与组织修复活性的生物材料在再生医学领域具有潜在应用前景.考虑到稀土元素Nd的荧光发光与光热双重特性,结合钙硅基(Ca-Si)生物材料优异的组织修复活性,有可能制备多功能组织损伤修复材料.本研究通过在硅酸钙中引入Nd元素,采用共沉淀方法及800℃以上煅烧,成功制备了Nd-Ca-Si基生物陶瓷粉体(Nd/C...     

Aptamer-conjugated gold nanostars for targeted cancer photothermal therapy

Photothermal therapy is a highly efficient and minimally invasive method for cancer therapy. To enhance the safe and effective effect of photothermal therapy, specific recognition of targeting cells and efficient direct heat transmission to cells for killing cells are quite important. In this work, aptamer-conjugated gold nanostars (Apt-AuNSs) used for targeted photothermal therapy were reported. AuNSs showed a higher photothermal conversion efficiency and excellent photostability, which has been used as a highly effective theranostic nanoprobe. Thiol-modified AS1411 aptamers, which showed the high targeting property for HeLa cells with overexpression of nucleolin, were conjugated to AuNSs through Au–S bond. In vitro toxicity assessments illustrated that Apt-AuNSs have low cytotoxicity and suitable for biological applications. Furthermore, the accumulation of Apt-AuNSs in HeLa cells was observed via TEM image. The targeted photothermal therapy in vitro and apoptosis assay results showed excellent anticancer effect. These results suggest that the targeted Apt-AuNSs exhibit great potential in selective photothermal therapy of cancer.     

Boron Dipyrromethene Nano‐Photosensitizers for Anticancer Phototherapies

As traditional phototherapy agents, boron dipyrromethene (BODIPY) photosensitizers have attracted increasing attention due to their high molar extinction coefficients, high phototherapy efficacy, and excellent photostability. After being formed into nanostructures, BODIPY‐containing nano‐photosensitizers show enhanced water solubility and biocompatibility as well as efficient tumor accumulation compared to BODIPY molecules. Hence, BODIPY nano‐photosensitizers demonstrate a promising potential for fighting cancer. This review contains three sections, classifying photodynamic therapy (PDT), photothermal therapy (PTT), and the combination of PDT and PTT based on BODIPY nano‐photosensitizers. It summarizes various BODIPY nano‐photosensitizers, which are prepared via different approaches including molecular precipitation, supramolecular interactions, and polymer encapsulation. In each section, the design strategies and working principles of these BODIPY nano‐photosensitizers are highlighted. In addition, the detailed in vitro and in vivo applications of these recently developed nano‐photosensitizers are discussed together with future challenges in this field, highlighting the potential of these promising nanoagents for new tumor phototherapies.     

Black Phosphorus Nanosheets as a Neuroprotective Nanomedicine for Neurodegenerative Disorder Therapy

Transition‐metal dyshomeostasis is recognized as a critical pathogenic factor at the onset and progression of neurodegenerative disorder (ND). Excess transition‐metal ions such as Cu²⁺ can catalyze the generation of cytotoxic reactive oxygen species and thereafter induce neuronal cell apoptosis. Exploring new chelating agents, which are not only capable of capturing excess redox‐active metal, but can also cross the blood–brain barrier (BBB), are highly desired for ND therapy. Herein, it is demonstrated that 2D black phosphorus (BP) nanosheets can capture Cu²⁺ efficiently and selectively to protect neuronal cells from Cu²⁺‐induced neurotoxicity. Moreover, both in vitro and in vivo studies show that the BBB permeability of BP nanosheets is significantly improved under near‐infrared laser irradiation due to their strong photothermal effect, which overcomes the drawback of conventional chelating agents. Furthermore, the excellent biocompatibility and stability guarantee the biosafety of BP in future clinical applications. Therefore, these features make BP nanosheets have the great potential to work as an efficient neuroprotective nanodrug for ND therapy.     

Facile Synthesis of Efficient Luminogens with AIE Features for Three-Photon Fluorescence Imaging of the Brain through the Intact Skull

Visualization of the brain in its native environment is important for understanding common brain diseases. Herein, bright luminogens with remarkable aggregation-induced emission (AIE) characteristics and high quantum yields of up to 42.6% in the solid state are synthesized through facile reaction routes. The synthesized molecule, namely BTF, shows ultrabright far-red/near-infrared emission and can be fabricated into AIE dots by a simple nanoprecipitation procedure. Due to their high brightness, large Stokes shift, good biocompatibility, satisfactory photostability, and large three-photon absorption cross section, the AIE dots can be utilized as efficient fluorescent nanoprobes for in vivo brain vascular imaging through the intact skull by a three-photon fluorescence microscopy imaging technique. This is the first example of using AIE dots for the visualization of the cerebral stroke process through the intact skull of a mouse with high penetration depth and good image contrast. Such good results are anticipated to open up a new venue in the development of efficient emitters with strong nonlinear optical effects for noninvasive bioimaging of living brain.     

Research progress on the luminescence of biomacromolecules

Luminescent materials show great potential in various applications.Traditional aggregation-induced emission(AIE)luminogens are mostly produced by complex organic synthesis and have poor hydrophilic-ity and biocompatibility,which limit their practical applications.Therefore,it is of great significance to develop fluorescent materials with good hydrophilicity and biocompatibility,and biomacromolecules with these properties have attracted our attention.Partial biomacromolecules can generate unique new fluorophores during the gelation process to obtain hydrogels with good fluorescence properties.In addi-tion,biomacromolecules can be modified with fluorescent groups to obtain fluorescent materials with excellent performance,thus improving the hydrophilicity and biocompatibility of fluorophore.In par-ticular,grafting aggregation-caused quenching(ACQ)luminogens onto biomacromolecules can even effectively inhibit the aggregation and self-quenching of luminogens.It is well known that aromatic biological macromolecules such as green fluorescent protein have intrinsic fluorescence.Intrinsic fluo-rescence is also observed in nonaromatic biological macromolecules without traditional chromophores such as chitosan,cellulose and sodium alginate.The luminescence of nonaromatic biomacromolecule can be rationalized by the clustering-triggered emission(CTE)mechanism,namely,clustering of nonconven-tional chromophores and subsequent electron overlap and conformation rigidification are accountable for the emssion.In this review,fluorescence gels obtained from biomacromolecules,biomacromolecules modified with fluorophores,and the intrinsic luminescence of biomacromolecular luminogens are assessed.This review will help to develop low-cost,biocompatible luminescent materials and has great significance for comprehending the luminescence of nonconventional luminophores and expanding the application of luminescent compounds.     

Molecular Engineering of an Organic NIR‐II Fluorophore with Aggregation‐Induced Emission Characteristics for In Vivo Imaging

Design and synthesis of new fluorophores with emission in the second near‐infrared window (NIR‐II, 1000–1700 nm) have fueled the advancement of in vivo fluorescence imaging. Organic NIR‐II probes particularly attract tremendous attention due to excellent stability and biocompatibility, which facilitate clinical translation. However, reported organic NIR‐II fluorescent agents often suffer from low quantum yield and complicated design. In this study, the acceptor unit of a known NIR‐I aggregation‐induced emission (AIE) luminogen (AIEgen) is molecularly engineered by varying a single atom from sulfur to selenium, leading to redshifted absorption and emission spectra. After formulation of the newly prepared AIEgen, the resultant AIE nanoparticles (referred as L897 NPs) have an emission tail extending to 1200 nm with a high quantum yield of 5.8%. Based on the L897 NPs, noninvasive vessel imaging and lymphatic imaging are achieved with high signal‐to‐background ratio and deep penetration. Furthermore, the L897 NPs can be used as good contrast agents for tumor imaging and image‐guided surgery due to the high tumor/normal tissue ratio, which peaks at 9.0 ± 0.6. This work suggests a simple strategy for designing and manufacturing NIR‐II AIEgens and demonstrates the potential of NIR‐II AIEgens in vessel, lymphatic, and tumor imaging.     

Bright Aggregation‐Induced‐Emission Dots for Targeted Synergetic NIR‐II Fluorescence and NIR‐I Photoacoustic Imaging of Orthotopic Brain Tumors

Precise diagnostics are of significant importance to the optimal treatment outcomes of patients bearing brain tumors. NIR‐II fluorescence imaging holds great promise for brain‐tumor diagnostics with deep penetration and high sensitivity. This requires the development of organic NIR‐II fluorescent agents with high quantum yield (QY), which is difficult to achieve. Herein, the design and synthesis of a new NIR‐II fluorescent molecule with aggregation‐induced‐emission (AIE) characteristics is reported for orthotopic brain‐tumor imaging. Encapsulation of the molecule in a polymer matrix yields AIE dots showing a very high QY of 6.2% with a large absorptivity of 10.2 L g^?1 cm^?1 at 740 nm and an emission maximum near 1000 nm. Further decoration of the AIE dots with c‐RGD yields targeted AIE dots, which afford specific and selective tumor uptake, with a high signal/background ratio of 4.4 and resolution up to 38 µm. The large NIR absorptivity of the AIE dots facilitates NIR‐I photoacoustic imaging with intrinsically deeper penetration than NIR‐II fluorescence imaging and, more importantly, precise tumor‐depth detection through intact scalp and skull. This research demonstrates the promise of NIR‐II AIE molecules and their dots in dual NIR‐II fluorescence and NIR‐I photoacoustic imaging for precise brain cancer diagnostics.