A Stable Open-Shell Conjugated Diradical Polymer with Ultra-High Photothermal Conversion Efficiency for NIR-Ⅱ Photo-Immunotherapy of Metastatic Tumor

Massive efforts have been concentrated on the advance of eminent near-infrared(NIR) photothermal materials(PTMs) in the NIR-Ⅱ window(1000–1700 nm), especially organic PTMs because of their intrinsic biological safety compared with inorganic PTMs. However, so far, only a few NIR-Ⅱresponsive organic PTMs was explored, and their photothermal conversion efficiencies(PCEs) still remain relatively low. Herein, donor–acceptor conjugated diradical polymers with open-shell characteristics are explored for synergistically photothermal immunotherapy of metastatic tumors in the NIR-Ⅱ window. By employing side-chain regulation, the conjugated diradical polymer TTB-2 with obvious NIR-Ⅱ absorption was developed, and its nanoparticles realize a record-breaking PCE of 87.7% upon NIR-Ⅱ light illustration. In vitro and in vivo experiments demonstrate that TTB-2 nanoparticles show good tumor photoablation with navigation of photoacoustic imaging in the NIR-Ⅱ window, without any side-effect. Moreover, by combining with PD-1 antibody,the pulmonary metastasis of breast cancer is high-effectively prevented by the efficient photo-immunity effect. Thus, this study explores superior PTMs for cancer metastasis theranostics in the NIR-Ⅱ window, offering a new horizon in developing radical-characteristic NIR-Ⅱ photothermal materials.

负载荧光分子的EVA乳胶用于NIR-Ⅱ指纹成像应用

NIR-Ⅱ荧光分子通常在固体状态下表现出聚集淬灭问题,严重阻碍了其在荧光传感领域的应用。本工作利用醋酸乙烯-乙烯共聚乳胶(EVA乳胶)聚合物易于改性的特点,采用共混干燥方法将NIR-Ⅱ荧光分子分散至EVA乳胶粉中,实现了其固态荧光抗淬灭的目的。此外,制备的NIR-Ⅱ-EVA乳胶粉通过喷壶喷洒的方式实现了简便、快速的NIR-Ⅱ指纹荧光显影应用。本研究为NIR-Ⅱ荧光分子的固态发光性质调控提供了新的策略,并拓展了EVA乳胶在生物信息传感等领域的应用潜力。

Deep learning enhanced NIR-Ⅱ volumetric imaging of whole mice vasculature

Fluorescence imaging through the second near-infrared window(NIR-Ⅱ,1000–1700 nm) allows in-depth imaging.However, current imaging systems use wide-field illumination and can only provide low-contrast 2D information, without depth resolution. Here, we systematically apply a light-sheet illumination, a time-gated detection, and a deep-learning algorithm to yield high-contrast high-resolution volumetric images. To achieve a large Fo V(field of view) and minimize the scattering effect, we generate a light sheet as thin as 100.5 μm with a Rayleigh length of 8 mm to yield an axial resolution of 220 μm. To further suppress the background, we time-gate to only detect long lifetime luminescence achieving a high contrast of up to 0.45 Icontrast. To enhance the resolution, we develop an algorithm based on profile protrusions detection and a deep neural network and distinguish vasculature from a low-contrast area of 0.07 Icontrast to resolve the 100μm small vessels. The system can rapidly scan a volume of view of 75 × 55 × 20 mm3and collect 750 images within 6mins. By adding a scattering-based modality to acquire the 3D surface profile of the mice skin, we reveal the whole volumetric vasculature network with clear depth resolution within more than 1 mm from the skin. High-contrast large-scale 3D animal imaging helps us expand a new dimension in NIR-Ⅱ imaging.

金纳米棒在NIR-Ⅱ区光热治疗中的研究进展

光热疗法(PTT)在癌症治疗领域是一种非常有前途的治疗方法.综述了近红外(NIR)光活化金纳米棒(Au NRs)在光热协同治疗肿瘤方面的最新进展.介绍了其在近红外一区(NIR-I)和近红外二区(NIR-Ⅱ)的光热潜力,及其在NIR-Ⅱ的窗口协同化学疗法(CT)、光动力学疗法(PDT)、化学动力学疗法(CDT)在对癌症的多模式治疗中的应用.此外,还讨论了该领域存在的挑战,为开发新型的NIR-Ⅱ光热剂提供了思路.

Research progress on rare earth up-conversion and near-infrared Ⅱ luminescence in biological applications

Rare earth luminescence has attracted widespread attention for several decades, among which nearinfrared(NIR) light-related up-conversion luminescence and NIR-Ⅱ luminescence are widely used in the biomedical field. The NIR-related luminescence is widely studied due to the excellent performance, such as good biocompatibility, deep tissue penetration depth, low self-fluorescence and minimal light damage to organisms. In this review, we mainly introduce the mechanism for rare earth up-conversion luminescence, NIR-Ⅱ luminescence and conclude their advantages compared with traditional luminescence.These excellent priorities provide the basis for NIR-related luminescence bioimaging in vivo. Additionally,we hilglight the scheme for the sensitive detection of substances in organisms and various methods for biological therapy. In spite of the existing research, it is outlined that NIR-related luminescence has great potential to be applied in different aspects, expanding perspectives and future challenges of research in related fields. Based on the current scientific achievements, this review can provide reference for research in the areas mentioned above, expand the research direction and arouse a broad interest in different disciplines to pay attention to rare earth luminescence.

Self-assembled amphiphilic NIR-Ⅱ emissive nano-micelles for imaging-guided photothermal therapy of colorectal cancer

Colorectal cancer(CRC) is one of the major causes of cancer-related mortality worldwide. Most near-infrared(NIR) agents used in clinical CRC treatment are at NIR-I(700–900 nm) window, which has limitations on deep tissue, and fluorescent probes in the second NIR(1,000–1,700 nm) allow high-resolution bioimaging with deep tissue penetration. However, existing NIR-II fluorophores used in clinical are still rare. Herein, based on shielding-donor-acceptor-donor-shielding(S-D-A-D-S) scaffold, we developed an organic small-molecule fluorophore IR-BTGP with NIR-II emission for imaging-guided photothermal therapy(PTT) in CRC mice model. Amphiphilic IR-BTGP can be self-assembled into spherical nano-micelles, which presents reliable water solubility and photothermal conversion efficiency(30.2%). In vitro experiments indicate that cancer cells treated with IRBTGP were significantly killed upon 808 nm light irradiation. Furthermore, in vivo NIR-II fluorescence imaging confirms that IR-BTGP accumulates in the tumor region. Remarkably, a significant tumor inhibition rate(78.5%) was observed in tumorbearing mice when treated with IR-BTGP plus 808 nm irradiation. Therefore, this work shows that IR-BTGP holds great promise as an NIR-II fluorescence imaging-guided PTT platform for CRC in the future.

Julolidinyl aza-BODIPYs as NIR-Ⅱ fluorophores for the bioimaging of nanocarriers

The aggregation-caused quenching(ACQ)rationale has been employed to improve the fluorescence imaging accuracy of nanocarriers by precluding free probe-derived interferences.However,its usefulness is undermined by limited penetration and low spatiotemporal resolution of NIR-Ⅰ(700-900 nm)bioimaging owing to absorption and diffraction by biological tissues and tissue-derived autofluorescence.This study aimed to develop ACQ-based NIR-Ⅱ(1000-1700 nm)probes to further improve the imaging resolution and accuracy.The strategy employed is to install highly planar and electron-rich julolidine into the 3,5-position of aza-BODIPY based on the larger substituent effects.The newly developed probes displayed remarkable photophysical properties,with intense absorption centered at approximately 850 nm and bright emission in the 950-1300 nm region.Compared with the NIR-Ⅰ counterpart P2,the NIR-Ⅱ probes demonstrated superior water sensitivity and quenching stability.ACQ1 and ACQ6 exhibited more promising ACQ effects with absolute fluorescence quenching at water fractions above 40% and higher quenching stability with less than 2.0% fluorescence reillumination in plasma after 24 h of incubation.Theoretical calculations verified that molecular planarity is more important than hydrophobicity for ACQ properties.Additionally,in vivo and ex vivo reillumination studies revealed less than 2.5% signal interference from prequenched ACQ1,in contrast to 15% for P2.

Cocktail nano-adjuvant enhanced cancer immunotherapy based on NIR-Ⅱ-triggered in-situ tumor vaccination

Second near-infrared(NIR-Ⅱ)light triggered in-situ tumor vaccination(ISTV)represents one of the most promising strategies in boosting the whole-body antitumor immunity.While most of previously developed nano-adjuvants for NIR-Ⅱ-triggered ISTV are“all-in-one”formulations,which may indiscriminately damage both the tumor cells and the immune cells,limiting the overall effect of immune response.To overcome this obstacle,we designed a“cocktail”nano-adjuvant by physically mixing hyaluronidases(HAase)-decorated gold nanostars(HA)for NIR-Ⅱlight triggered in situ production of tumor-associated antigens and CpG functionalized gold nanospheres(CA)for immune cells activation.Compared to“all-in-one”formulation,the“cocktail”nano-adjuvants displayed a significantly stronger immune response on NIR-Ⅱlight induced dendritic cells(DCs)mutation and T cells differentiation,greater effect on tumor-growth inhibition,and higher efficacy in inhibition of pulmonary metastases.What is more,increasing the molar ratio of HA to CA led to an enhanced anticancer immune responses.This study highlight the nano-adjuvant formulation effects on the treatment of tumors with multiple targets.

Ultra-homogeneous Cu_(2-x)Se nanoparticles as near-infraredⅡplasmonic phototheranstics for photothermal/chemodynamic synergistic therapy of liver cancer

Laser mediated photothermal/chemodynamic co-therapy is widely applied for anti-cancer treatment due to its good therapeutic effect.However,the laser wavelength for effectively targeting deep tumor tissues can decide whether or not it is a key premise of irradiation treatment.In this study,a super-homogenous and highly dispersive spherical nanoparticle Cu_(2-x)Se was prepared,which displayed a strong surface plasmon resonance(SPR)peak in the near-infrared region(NIR)-Ⅱand high Fenton catalytic efficiency.The results of in vitro experiments showed that Cu_(2-x)Se nanoparticles exhibited high photothermal conversion efficiency under the excitation of NIR-Ⅱlaser irradiation,which significantly improved its ability to produce OH.In a tumor-bearing mouse model,the combination of Cu_(2-x)Se and photothermal/chemodynamic co-therapy guided by the real-time photoacoustic imaging in the NIR-Ⅱcould effectively inhibit tumor growth and exhibit good in vivo/in vitro biocompatibility.In summary,this Cu_(2-x)Se nanoparticle-based NIR-Ⅱlaser-mediated photothermal/chemodynamic co-therapy strategy is expected to provide a new option for the diagnosis and treatment of liver cancer.

可见光到近红外Ⅱ区内宽领域可调发射的芘基共晶

有机材料的可变发光在波导和显示应用方面具有广泛的潜力.然而,基于单一有机分子体系实现从可见光到近红外区域的大范围发光调节仍然是一项挑战.本文介绍了一系列基于芘的同构共晶体,可提供从可见光到近红外Ⅱ区的可调发射.它们的能级是通过引入电荷转移和无氟芳烃-全氟芳烃相互作用而定制的.令人印象深刻的是,这项工作中的有机微晶可以成功地应用于微观层面的多色波导以及宏观层面的二维码显示,为先进的光子学开辟了新的道路.这项工作为获得400至1100 nm的有机晶体提供了一种简单而有效的方法,从而为制造多种光电子学的核心材料提供了可能性.

Emerging NIR-Ⅱ Luminescent Gold Nanoclusters for In Vivo Bioimaging

Gold nanoclusters(AuNCs)with near-infraredⅡ(NIR-Ⅱ)photoluminescence(PL)have emerged as novel bioimaging probes for in vivo disease diagnosis.So far,it still lacks a systematic review focusing on the synthesis,PL tuning,and in vivo imaging of NIR-Ⅱluminescent AuNCs.In this review,we briefly introduce the synthesis of NIR-Ⅱluminescent AuNCs using various surface ligands.We discuss the origins and properties of NIR-ⅡPL in AuNCs,and summarize the strategies for improving and/or tuning NIR-ⅡPL emissions.We also provide an overview of the recent progress in the application of AuNCs in tumor-targeted imaging,molecular imaging,and other areas(such as the sensitive imaging of bones,vessels,lymph nodes,etc.).Finally,we present the prospects and challenges in the field of NIR-Ⅱluminescent AuNCs and related imaging applications,expecting to offer comprehensive understanding of this field,and thereby deepening and broadening the biological application of AuNCs.

Iron-based and BRD_(4)-downregulated strategy for amplified ferroptosis based on pH-sensitive/NIR-Ⅱ-boosted nano-matchbox

Ferroptosis(FPT),a novel form of programmed cell death,is characterized by overwhelming iron/reactive oxygen species(ROS)-dependent accumulation of lipid peroxidation(LPO).However,the insufficiency of endogenous iron and ROS level limited the FPT therapeutic efficacy to a large extent.To overcome this obstacle,the bromodomain-containing protein 4(BRD_(4))-inhibitor(+)-JQ1(JQ1)and iron-supplement ferric ammonium citrate(FAC)-loaded gold nanorods(GNRs)are encapsulated into the zeolitic imidazolate framework-8(ZIF-8)to form matchbox-like GNRs@JF/ZIF-8 for the amplified FPT therapy.The existence of matchbox(ZIF-8)is stable in physiologically neutral conditions but degradable in acidic environment,which could prevent the loaded agents from prematurely reacting.Moreover,GNRs as the drug-carriers induce the photothermal therapy(PTT)effect under the irradiation of near-infraredⅡ(NIR-Ⅱ)light owing to the absorption by localized surface plasmon resonance(LSPR),while the hyperthermia also boosts the JQ1 and FAC releasing in the tumor microenvironment(TME).On one hand,the FAC-induced Fenton/Fenton-like reactions in TME can simultaneously generate iron(Fe^(3+)/Fe^(2+))and ROS to initiate the FPT treatment by LPO elevation.On the other hand,JQ1 as a small molecule inhibitor of BRD_(4)protein can amplify FPT through downregulating the expression of glutathione peroxidase 4(GPX4),thus inhibiting the ROS elimination and leading to the LPO accumulation.Both in vitro and in vivo studies reveal that this p H-sensitive nano-matchbox achieves obvious suppression of tumor growth with good biosafety and biocompatibility.As a result,our study points out a PTT combined iron-based/BRD_(4)-downregulated strategy for amplified ferrotherapy which also opens the door of future exploitation of ferrotherapy systems.

NIR-Ⅱabsorbing organic nanoagents for photoacoustic imaging and photothermal therapy

Near-infrared(NIR)absorbing materials hold great potential in biomedical applications,such as fluorescence imaging(FLI),photoacoustic imaging(PAI),photodynamic therapy(PDT),and photothermal therapy(PTT).Generally,these materials can be classified into two main categories based on their absorbing wavelengths:the first NIR(NIR-I)(~650–950 nm)absorbing materials and the second NIR(NIR-Ⅱ)(~1000–1700 nm)absorbing materials.Due to the reduced absorption and scattering of NIR-Ⅱlight in tissue compared to NIR-Ⅰlight,NIR-Ⅱabsorbing materials enable imaging and therapy with improved contrast and deepened penetration,which is in favor of practical applications.Various inorganic materials have been developed for NIR-Ⅱphototheranostics in recent years.However,the non-biodegradability and potential toxicity of these materials hinder their further clinical trans-lation.Biocompatible organic materials with potential biodegradability as well as tailored optical property are thus more desired.In this review,we sum-marize the recent advances of NIR-Ⅱabsorbing organic nanoagents(ONAs)based on small molecules(SMs)and conjugated polymers(CPs)for PAI and PTT and show our perspectives on future challenges and development of these materials.

Lanthanide-doped near-infrared Ⅱ luminescent nanoprobes for bioapplications

Luminescent biosensing in the second nearinfrared(NIR-II) region is featured with superior spatial resolution and high penetration depth by virtue of the suppressed scattering of long-wavelength photons. Hitherto, the reported NIR-II nanoprobes are mostly based on carbon nanotubes, organic fluorophores or semiconducting quantum dots. As an alternative, trivalent lanthanide ions(Ln3+) doped nanoparticles have been emerging as a novel class of promising nanoprobes. In this review, we highlight the recent progress in the design of highly efficient Ln3+-doped NIR-II nanoparticles towards their emerging bioapplications, with an emphasis on autofluorescence-free bioimaging, sensitive bioassay, and accurate temperature sensing. Moreover, some efforts and challenges towards this rapidly expanding field are envisioned.

Highly Efficient Near-Infrared Ⅱ Electrochemiluminescence from NaYbF_(4) Core Mesoporous Silica Shell Nanoparticles

Due to less interference in biological imaging,nanomaterials with second near-infrared(NIR-II)window(950–1700 nm)emission have received tremendous attention.However,no reports on NIR-Ⅱ electrochemiluminescence(ECL)imaging exist because of the lack of high-efficiency NIR-Ⅱ ECL luminophores.Herein,we designed and synthesized a NaYbF4@SiO_(2) core–shell nanoparticle for the first time.

可激活的NIR-Ⅱ探针用于肿瘤成像

波长位于1000~1700 nm之间的近红外窗口,通常被称为第二近红外(NIR-Ⅱ)窗口,在生物成像方面(荧光成像、光声成像等),该窗口展现出强大的吸引力。相比在可见光(400~700 nm)区域和第一近红外(NIR-Ⅰ,700~900 nm)窗口的传统成像,NIR-Ⅱ生物成像提供了分辨率高和穿透深度深等优点。但是,目前大多数"always-on"探针,并不能实现更高的信噪比。肿瘤微环境响应型智能药物的成像只在肿瘤中触发,可以克服这一局限性。因此,应充分结合肿瘤微环境和NIR-Ⅱ智能响应探针,充分发挥两者的优势,提高肿瘤的精准诊断。本文从不同的病理参数综述了可激活的NIR-Ⅱ荧光探针在生物成像中的最新研究进展,并对这一新兴的领域所面临的机遇和挑战提出看法。

三元共轭聚合物用于NIR-Ⅱ荧光成像及光热/光动力联合治疗

为获得同时具有光热性能、光动力性能及近红外二区(NIR-Ⅱ,1000-1700 nm)荧光发射的共轭聚合物,将一种电子受体单元和2种电子供体单元进行共聚得到一种新型三元共轭聚合物,进一步利用两亲性Pluronic F127作为包覆材料,通过简单的纳米沉淀方法制备得到基于该共轭聚合物的水溶性纳米颗粒.该纳米颗粒具有优异的生物相容性、较好的稳定性、高的近红外一区(NIR-Ⅰ,650~900 nm)光学吸收及NIR-Ⅱ荧光发射能力.在单一激光照射下,该纳米颗粒可以同时产生过高热、活性氧及NIR-Ⅱ荧光信号,可用于NIR-Ⅱ荧光成像指导下的肿瘤光热/光动力联合治疗.

Lanthanide-doped rare earth nanoparticles for nearinfrared-Ⅱimaging and cancer therapy

The optical nanoprobes with emissions in the second near-infrared window(NIR-Ⅱ,1000-1700 nm)show low tissue autofluorescence and photon scattering;therefore,they provide high spatial resolution and acceptable tissue penetration depth.These advantages make them appropriate for in vivo applications,including bioimaging,NIR-Ⅱtriggered disease therapy,and even on-site efficacy monitoring.Among the various developed NIR-Ⅱfluorescence probes,lanthanide-doped nanoparticles(LDNPs)exhibit high photo stability and narrow emission bandwidths with long photoluminescence lifetimes and low cytotoxicity;therefore,they have been widely studied in the biomedical field.This review summarizes the typical compositions and optical properties of recently developed NIR-Ⅱemitting LDNPs.Their applications in in vivo NIR-Ⅱbioimaging and cancer therapy are reviewed.The perspectives and challenges of NIR-ⅡLDNPs are also discussed.

Construction of a 980 nm laser-activated Pt(Ⅱ)metallacycle nanosystem for efficient and safe photo-induced bacteria sterilization

Although metal-based chemical agents have demonstrated promising bacteriostatic effects in phototherapy,their short excitation/emission wavelengths and inadequate phototherapy efficiencies make their application in vivo difficult.We therefore synthesized a novel Pt(Ⅱ)metallacycle(Pt1110)that can be activated with a 980 nm laser for photodiagnosis/treatment in deep tissue.We found that Pt1110 significantly improved photothermal conversion(95%improvement)and ^(1)O_(2) generation(ΦΔ75%increase)compared to the ligand itself 1 and was well capable of light-induced sterilization under safe laser irradiation(0.72 W/cm^(2)).In addition,Pt1110 has little to no toxicity to cells.After incorporated into liposome,Pt1110 NPs was effective in wound healing in infection and keratitis models upon laser irradiation,which was accurately observed by NIR-Ⅱfluorescence imaging.This novel metal-coordinated supramolecular material has a potential to become a universal platform for phototherapy in deep tissue.

Dual activated NIR-Ⅱ fluorescence and photoacoustic imaging-guided cancer chemo-radiotherapy using hybrid plasmonic-fluorescent assemblies

Multimodal imaging in the second near-infrared window(NIR-II)guided cancer therapy is a highly precise and efficient cancer theranostic strategy.However,it is still a challenge to develop activated NIR-II optical imaging and therapy agents.In this study,we develop a pH-responsive hybrid plasmonic-fluorescent vesicle by self-assembly of amphiphilic plasmonic nanogapped gold nanorod(AuNNR)and fluorescent down-conversion nanoparticles(DCNP)(AuNNR-DCNP Ve),showing remarkable and activated NIR-II fluorescence(FL)/NIR-II photoacoustic(PA)imaging performances.The hybrid vesicle also exhibited superior loading capacity of doxorubicin as a superior drug carrier and efficient radiosensitizer for X-ray-induced radiotherapy.Interestingly,the accumulated hybrid AuNNR-DCNP Ve in the tumor resulted in a recovery of NIR-II FL imaging signal and a variation in NIR-II PA imaging signal.Dual activated NIR-II PA and FL imaging of the hybrid vesicle could trace drug release and precisely guided cancer radiotherapy to ultimately reduce the side effects to healthy tissue.