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.

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.

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.

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.

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.

Chiral NIR-Ⅱ fluorescent Ag_(2)S quantum dots with stereospecific biological interactions and tumor accumulation behaviors

Near-infrared Ⅱ(NIR-Ⅱ)fluorescent nanoprobes hold great potential for biomedical applications.Elucidating the relationship between surface properties of NIR-Ⅱ nanoprobes and their biological behaviors is particularly important for future probe design and their performance optimization.Despite the rapid development of NIR-Ⅱ nanoprobes,the distinct role of surface chirality on their biological fates has rarely been exploited.Herein,chiral NIR-Ⅱ fluorescent Ag_(2)S quantum dots(QDs)are synthesized to investigate the relationship between their chirality and biological functions at both in vitro and in vivo levels.D-/L-Ag_(2)S QDs exhibit significant differences on their interactions with serum proteins,which further affect the cellular uptake.As a result,D-Ag_(2)S QDs can be internalized with higher efficiency(over 2-fold)than that of L-Ag_(2)S QDs.Moreover,in vivo studies reveal that the chirality determines the primary localization of these chiral QDs,where a more efficient renal elimination of D-Ag_(2)S QDs was observed than that of L-Ag_(2)S QDs.Importantly,D-Ag_(2)S QDs show preferential accumulation in tumor region than that of L-Ag_(2)S QDs in orthotopic kidney tumor model,which points out a new avenue of enhancing targeting capabilities of nanoprobes by engineering their surface chirality.

New NIR-Ⅱ dyes without a benzobisthiadiazole core

Fluorescent NIR-Ⅱ imaging has a wide range of benefits not offered by other imaging modalities for biomedical applications, derived from its combination of high spatial and temporal resolution due to reduced photon absorption, scattering and tissue auto-fluorescence. Compared to the well-studied NIR-Ⅰ small-molecule fluorophores, the structures of NIR-Ⅱ fluorophores are scarce. To date, the main fluorophore units are composed of conjugated π system with a benzobisthiadiazole（BBTD） core and donor-acceptor-donor（D-A-D） structure. Herein, researchers Yang et al. and Zhang et al. have reported new NIR-Ⅱ probes ECX and FD-1080 respectively without a BBTD core which are highlighted.

Building multipurpose nano-toolkit by rationally decorating NIR-Ⅱ fluorophore to meet the needs of tumor diagnosis and treatment

Phototheranostics have attracted tremendous attention in cancer diagnosis and treatment because of the noninvasiveness and promising effectiveness.Developing advanced phototheranostic agents with long emission wavelength,excellent biocompatibility,great tumor-targeting capability,and efficient therapeutic effect is highly desirable.However,the mutual constraint between imaging and therapeutic functions usually hinders their wide applications in biomedical field.To balance this contradiction,we herein rationally designed and synthesized three novel tumor-targeted NIR-Ⅱ probes(QR-2PEG_(321),QR-2PEG_(1000),and QR-2PEG_(5000)) by conjugating three different chain lengths of PEG onto an integrin α_(v)β_(3)-targeted NIR-Ⅱ heptamethine cyanine fluorophore,respectively.In virtue of the essential amphiphilic characteristics of PEG polymers,these probes display various degree of aggregation in aqueous buffer accompanying with differential NIR-Ⅱ imaging and photothermal(PTT) therapeutic performance.Both in vitro and in vivo results have demonstrated that probe QR-2PEG_(5000) has the best NIR-Ⅱ imaging performance with prominent renal clearance,whereas QR-2PEG_(321)possesses excellent photoacoustic signal as well as PTT effect,which undoubtedly provides a promising toolbox for tumor diagnosis and therapy.We thus envision that these synthesized probes have great potential to be explored as a toolkit for precise diagnosis and treatment of malignant tumors.

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.

High brightness NIR-Ⅱ nanofluorophores based on fused-ring acceptor molecules

It is challenging to develop molecular fluorophores in the second near-infrared(NIR-Ⅱ)window with long wavelength emission and high brightness,which can improve the performance of biological imaging.Herein,we report a molecular engineering approach to afford NIR-Ⅱ fluorophores with these merits based on fused-ring acceptor(FRA)molecules.Dioctyl 3,4-propylenedioxy thiophene(PDOT-C8)is utilized as the bridging donor to replace 3-ethylhexyloxy thiophene(3-EHOT),leading to more than 20 times enhancement of brightness.The nanofluorophores(NFs)based on the optimized CPTIC-4F molecule exhibit an emission peak of 1,110 nm with a fluorescence quantum yield(QY)of 0.39%(QY of IR-26 is 0.050%in dichloroethane as reference)and peak absorption coefficient of 14.5 x 10^4 M^-1·cm^-1 in aqueous solutions,which are significantly higher than those of 3-EHOT based COTIC-4F NFs.It is found that PDOT-C8 can weaken intermolecular aggregation,enhance protection of molecular backbone from water,and decrease backbone distortion,beneficial for the high brightness.Compared with indocyanine green with same injection dose,CPTIC-4F NFs show 10 times higher signal-to-background ratio for whole body vessels imaging at 1,300 nm long pass filters.

A facile phototheranostic nanoplatform integrating NIR-Ⅱ fluorescence/PA bimodal imaging and image-guided surgery/PTT combinational therapy for improved antitumor efcacy

Phototheranostic with highly integrated functions is an attractive platform for cancer management. It remains challenging to develop a facile phototheranostic platform with complementary bimodal imaging and combinational therapy capacity. Herein, the small-molecule cyanine IR780 loaded liposomes have been harnessed as a nanoplatform to simultaneously realize photoacoustic(PA)/the second near-infrared window(NIR-Ⅱ) fluorescence imaging and image-guided surgery/adjuvant photothermal therapy(PTT).This nanoplatform exhibits attractive properties like uniform controllable size, stable dispersibility, NIR-Ⅱ fluorescence emission, photothermal conversion, and biocompatibility. Benefiting from the complementary PA/NIR-Ⅱ fluorescence bimodal imaging, this nanoplatform was successfully applied in precise vasculature delineation and tumor diagnosis. Interestingly, the tumor was clearly detected by NIR-Ⅱ fluorescence imaging with the highest tumor-to-normal-tissue ratio up to 12.69, while signal interference from the liver was significantly reduced, due to the difference in the elimination rate of the nanoplatform in the liver and tumor. Under the precise guidance of the image, the tumor was accurately resected, and the simulated residual lesion after surgery was completely ablated by adjuvant PTT. This combined therapy showed improved antitumor efcacy over the individual surgery or PTT. This work develops a facile phototheranostic nanoplatform with great significance in accurately diagnosing and effectively treating tumors using simple NIR light irradiation.

Mesoporous radiosensitized nanoprobe for enhanced NIR-Ⅱ photoacoustic imaging-guided accurate radio-chemotherapy

Oxygen deficiency is a major obstacle to hypoxic-related cancer theranostics,and developing the oxygen production nanoplatforms received the widespread attention.However,it is remaining a challenge to structure a nanoplatform with hypoxia alleviation effect and imaging-guided cancer radiotherapy.Herein,we present a novel theranostics nanoplatform(Au NPs/UCNPs/WO_(3)@C)comprising of tungsten trioxide(WO3)that loaded gold nanoparticles(Au NPs)and up-conversion nanoparticles(UCNPs)for improved photoacoustic(PA)imaging performance in the second near infrared window(NIR-Ⅱ,900-1,700 nm).Au NPs/UCNPs/WO_(3)@C exhibited superior oxygen-generation effect and doxorubicin loading capacity,thus serving as an efficient radiosensitizer for radio-chemo anti-cancer therapy.Importantly,the accumulated Au NPs/UCNPs/WO_(3)@C in the tumor region led to the increased NIR-Ⅱ PA imaging signal and the blood oxygen saturation signal,which could enhance radiation sensitivity and accurately guiding cancer radiotherapy to reduce side effects on normal tissues.This study with proof-of-concept confirmed the multifaceted characteristics and encouraging potential of biomimetic Au NPs/UCNPs/WO_(3)@C for NIR-Ⅱ PA imaging-guided tumor therapeutics.

NIR-Ⅱprobe modified by poly(L-lysine)with efficient ovalbumin delivery for dendritic cell tracking

Dendritic cell(DC)vaccine is an effective strategy for cancer immunotherapy by carrying antigen into DCs and migrating these DCs to drain lymph nodes after inoculation.In this article,second near-infrared window(NIR-II)fluorescent nanoparticles have been used to uptake antigen and activate DCs.Ovalbumin(OVA),an antigen for immunization,can be loaded on the surface of these NIR-II fluorescent nanoparticles via electrostatic interaction by virtue of their functionalized poly(L-lysine)(PLL),which exhibits biocompatibility and strong selective interaction with OVA.In addition,these antigen-loaded complexes can efficiently be engulfed by immature DCs to induce DC maturation and cytokine secretion.After subcutaneous injection,highly sensitive NIR-II fluorescence signal from nanoparticles indicates that nanoparticle-labeled DCs can successfully migrate into lymph nodes in vivo,showing great promise in immunotherapy against cancer.

NIR-Ⅱ fluorescence/photoacoustic imaging of ovarian cancer and peritoneal metastasis

Ovarian cancer is a global problem,and is typically diagnosed in the middle or late stages,with a mysterious abdominal mass or atypical abdominal metastases due to the lack of specific initial diagnostic methods.Dual-modal near-infrared Ⅱ(NIR-Ⅱ,1,000–1,700 nm)fluorescence/photoacoustic imaging has great potential in early ovarian cancer diagnosis and image-guided surgery due to its high sensitivity and deep penetration.Herein,we report a novel organic NIR-Ⅱ dye(H10)with excellent aggregation-induced-emission(AIE)characteristics(I/I0>1.6)utilizing a selenadiazolo-[3,4-f]benzo[c][1,2,5]thiadiazole(ST)-based building block.Then,water-soluble and biocompatible H10@follicle-stimulating hormone(H10@FSH)dots with superior optical/photoacoustic properties and a tenfold increase in ovarian-specific targeting ability were synthesized.Finally,for the first time,in vivo dual-mode NIR-Ⅱ fluorescent/photoacoustic(PA)imaging and image-guided surgery of patient-derived tumor xenograft(PDTX)and micro-metastatic abdominal ovarian cancer lesions were investigated.This novel strategy will establish a new method for early detection of ovarian cancer and significantly improve the prognosis of ovarian cancer patients.

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.