动脉粥样硬化光学成像探针研究进展

心血管疾病(Cardiovascular disease, CVD)是全球疾病致死的主要原因之一. 动脉粥样硬化(Atherosclerosis, AS)是引发各种CVD的首要危险因素, 其发生发展通常经历持续的慢性炎症过程. 因此, 及时高效地检测AS, 对于早期评估、 诊断和治疗CVD具有重要临床意义. 光学探针成像拥有极高的灵敏度和空间分辨率以及超快的信号采集处理速度, 被广泛应用于生物医学检测与成像. 本文综合评述了6种常见用于AS成像的光学探针, 涉及小分子荧光探针、 聚集诱导发光(Aggregate-induced emission, AIE)纳米探针、 量子点探针、 上转换纳米探针、 光声探针和多模态探针等; 并对各种探针的优缺点进行了分析比较. 在此基础上, 展望了光学探针在AS成像领域的发展前景, 并提出了相应建议.     

激活型有机光声造影剂的应用

光声(PA)成像作为一种结合了光学和声学成像优势的新型成像方式,具有深层组织穿透和高空间分辨率等优点,在重大疾病的早期影像诊断方面有着巨大的应用前景.然而传统的PA造影剂依然存在信噪比低、选择性及特异性差等不足,容易产生假阳性诊断结果.激活型PA造影剂可以有效的降低背景噪声,并提升成像的灵敏度和特异性,是目前PA造影剂...     

近红外二区活体荧光成像在肿瘤诊疗中的应用

由于具备组织穿透深度深和时空分辨率高等优势, 近年来近红外二区(Near-infrared-Ⅱ, NIR-Ⅱ, 1000~1700 nm)荧光成像技术得到了快速发展, 其在肿瘤临床诊断和治疗的潜力更是引发了广泛关注. 本文首先阐释了NIR-Ⅱ窗口荧光成像的原理及其优势, 随后根据结构分类归纳总结了现有荧光团的特征, 重点介绍了荧光探针在性能优化上的进展以及在肿瘤早期检测、 术中导航和光疗中的应用, 最后讨论了现有NIR-Ⅱ 荧光探针的局限以及临床转化面临的挑战, 并对未来的发展方向进行了展望.     

A Class of Activatable NIR-II Photoacoustic Dyes for High-Contrast Bioimaging

Photoacoustic (PA) imaging is emerging as one of the important non-invasive imaging techniques in biomedical research. Small molecule- second near-infrared window (NIR-II) PA dyes combined with imaging data can provide comprehensive and in-depth in vivo physiological and pathological information. However, the NIR-II PA dyes usually exhibit “always-on” properties due to the lack of a readily optically tunable group, which hinders the further applications in vivo. Herein, a novel class of dyes GX have been designed and synthesized as an activatable NIR-II PA platform, in which the absorption/emission wavelength of GX-5 extends up to 1082/1360 nm. Importantly, the GX dyes have a strong tissue penetration depth and high-resolution for the mouse vasculature structures in NIR-II PA 3D imaging and high signal-to-noise ratio in NIR-II fluorescence (FL) imaging. Furthermore, to demonstrate the applicability of GX dyes, the first NIR-II PA probe GX-5-CO activated by carbon monoxide (CO) was engineered and employed to reveal the enhancement of the CO levels in the hypertensive mice by high-contrast NIR-II PA and FL imaging. We expect that many derivatives of GX dyes will be developed to afford versatile NIR-II PA platforms for designing a wide variety activatable NIR-II PA probes as biomedical tools.     

基于聚集诱导发光荧光探针的细胞成像研究进展

荧光探针是化学传感技术领域在20世纪末的一项重大发现,具有合成简单、灵敏度高、选择性好、响应时间短、可视化高等优点。 将具有聚集诱导发光现象(AIE)特征的荧光基团与具有生物相容性的高分子结合起来,使得荧光材料具有毒性低、光稳定性好、生物相容性好等特点。 在分子、离子检测和细胞成像技术中得到广泛的研究和应用。 本文综述了细胞质成像、细胞膜成像、线粒体成像、溶酶体成像、脂滴成像、细胞核成像、细胞核和线粒体双靶向性成像的荧光探针,并对其应用前景做了展望。     

用于生物标记的半导体量子点研究

半导体量子点的独特光学性质使之成为理想的荧光探针材料,在生物医学领域具有广阔的应用前景.本文评述了目前量子点合成、表面修饰、结合生物分子的方法,以及半导体量子点在生物标记应用中相对于传统有机染料的优点.     

基于低相干干涉的透镜厚度测量及生物影像研究进展

低相干光干涉测量技术作为重要的非接触测量方法之一,由于具有结构简单、测量速度快及分辨率高的优点,在光学系统的非接触测量及生物医学影像等前沿领域具有广阔的应用前景。本文对透镜组的光学元件中心厚度及空气间隔的非接触测量技术进行了总结,简述了基于OCT的生物医学影像方面研究现状,重点论述基于低相干光干涉法测量原理和研究进展,对比分析相关研究方法的优缺点和创新之处,并从系统结构和应用范围的角度对低相干干涉测量技术的发展趋势作了展望。     

64Cu radiolabeled nanomaterials for positron emission tomography (PET) imaging

The prevalence of positron emission tomography (PET) imaging has advanced biomedical applications for its ultrahigh sensitivity, deep tissue penetration and quantitative visualization of diseases in vivo. ⁶⁴Cu with ideal half-life and decay characteristics has been designed as radioactive probes for disease diagnosis. The currently reported ⁶⁴Cu-labeled nanomaterials have the advantages of long circulation time in serum, good biocompatibility and mature preparation methods, and have been used in vivo PET imaging, biodistribution and pharmacokinetic monitoring, and imaging guided therapy. At the same time, suitable carrier characteristics and radiolabeling strategies are particularly important in the ⁶⁴Cu PET imaging process. In this review, we summarize different imaging probe designs and ⁶⁴Cu radiolabeling strategies, as well as their eventual applications in biomedicine. The potential challenges and prospects of ⁶⁴Cu labeled nanomaterials are also described, which provides broad prospects for radiolabeling strategies and further applications.     

An Extended NIR-II Superior Imaging Window from 1500 to 1900 nm for High-Resolution In Vivo Multiplexed Imaging Based on Lanthanide Nanocrystals

High-resolution in vivo optical multiplexing in second near-infrared window (NIR-II, 1000–1700 nm) is vital to biomedical research. Presently, limited by bio-tissue scattering, only luminescent probes located at NIR-IIb (1500–1700 nm) window can provide high-resolution in vivo multiplexed imaging. However, the number of available luminescent probes in this narrow NIR-IIb region is limited, which hampers the available multiplexed channels of in vivo imaging. To overcome the above challenges, through theoretical simulation we expanded the conventional NIR-IIb window to NIR-II long-wavelength (NIR-II-L, 1500–1900 nm) window on the basis of photon-scattering and water-absorption. We developed a series of novel lanthanide luminescent nanoprobes with emission wavelengths from 1852 nm to 2842 nm. NIR-II-L nanoprobes enabled high-resolution in vivo dynamic multiplexed imaging on blood vessels and intestines, and provided multi-channels imaging on lymph tubes, tumors and intestines. The proposed NIR-II-L probes without mutual interference are powerful tools for high-contrast in vivo multiplexed detection, which holds promise for revealing physiological process in living body.     

Introduction to Infrared and Raman-Based Biomedical Molecular Imaging and Comparison with Other Modalities

Molecular imaging has rapidly developed to answer the need of image contrast in medical diagnostic imaging to go beyond morphological information to include functional differences in imaged tissues at the cellular and molecular levels. Vibrational (infrared (IR) and Raman) imaging has rapidly emerged among the molecular imaging modalities available, due to its label-free combination of high spatial resolution with chemical specificity. This article presents the physical basis of vibrational spectroscopy and imaging, followed by illustration of their preclinical in vitro applications in body fluids and cells, ex vivo tissues and in vivo small animals and ending with a brief discussion of their clinical translation. After comparing the advantages and disadvantages of IR/Raman imaging with the other main modalities, such as magnetic resonance imaging (MRI), computed tomography (CT), positron emission tomography/single-photon emission-computed tomography (PET/SPECT), ultrasound (US) and photoacoustic imaging (PAI), the design of multimodal probes combining vibrational imaging with other modalities is discussed, illustrated by some preclinical proof-of-concept examples.     

Blending Low-Frequency Vibrations and Push–Pull Effects Affords Superior Photoacoustic Imaging Agents

Photoacoustic imaging (PAI), a state-of-the-art noninvasive in vivo imaging technique, has been widely used in clinical disease diagnosis. However, the design of high-performance PAI agents with three key characteristics, i.e., near-infrared (NIR) absorption (λ_abs>800 nm), intense PA signals, and excellent photostability, remains a challenging goal. Herein, we present a facile but effective approach for engineering PAI agents by amplifying intramolecular low-frequency vibrations and enhancing the push-pull effect. As a demonstration of this blended approach, we constructed a PAI agent ( BDP1-NEt₂ ) based on the boron-dipyrromethene (BODIPY) scaffold. Compared with indocyanine green (ICG, an FDA-approved organic dye widely utilized in PAI studies; λ_abs=788 nm), BDP1-NEt₂ exhibited a UV/Vis-NIR spectrum peaked at 825 nm, superior in vivo PA signal intensity and outstanding stability to offer improved tumor diagnostics. We believe this work provides a promising strategy to develop the next generation of PAI agents.     

Semiconducting polymer dots as near‐infrared fluorescent probes for bioimaging and sensing

In recent years, semiconducting polymer dots (Pdots) have emerged as a new type of ultrabright fluorescent probes, which have been proved to be very useful for biomedical imaging. Pdots possess several exceptional advantages including high fluorescence brightness, fast radiative rate, excellent photostability, and negligible cytotoxicity. Among these new types of Pdots, the near‐infrared (NIR) fluorescent Pdots appear to be the most urgent and important owing to their promising deep‐tissue imaging in the clinic. This mini‐review highlights the recent progress in the design of NIR‐emitting Pdots and their biomedical applications both in vitro and in vivo.     

Activatable Molecular Probes for Second Near‐Infrared Fluorescence,Chemiluminescence, and Photoacoustic Imaging

Optical imaging plays a crucial role in biomedicine. However, due to strong light scattering and autofluorescence in biological tissue between 650–900 nm, conventional optical imaging often has a poor signal‐to‐background ratio and shallow penetration depth, which limits its ability in deep‐tissue in vivo imaging. Second near‐infrared fluorescence, chemiluminescence, and photoacoustic imaging modalities mitigate these issues by their respective advantages of minimized light scattering, eliminated external excitation, and ultrasound detection. To enable disease detection, activatable molecular probes (AMPs) with the ability to change their second near‐infrared fluorescence, chemiluminescence, or photoacoustic signals in response to a biomarker have been developed. This Minireview summarizes the molecular design strategies, sensing mechanisms, and imaging applications of AMPs. The potential challenges and perspectives of AMPs in deep‐tissue imaging are also discussed.     

Localized surface plasmon resonance properties and biomedical applications of copper selenide nanomaterials

Nanomaterials with localized surface plasmon resonance (LSPR) locating in the near-infrared region have broad application prospects in the field of biomedicine. However, the biggest problem that limits the biomedical application of such nanomaterials lies in two aspects: First, the potential long-term in vivo toxicity caused by the metabolism of many nanomaterials with LSPR effect; Second, most of current nanomaterials with LSPR effect are difficult to achieve LSPR wavelength tunability in the near-infrared region to adapt to different biomedical applications. Copper selenide nanomaterials are composed of selenium and copper, which are necessary nutrient elements for human life. Because of the active and flexible chemical properties of selenium and copper, copper selenide nanomaterials can not only be effectively degraded and utilized in human body, but also be endowed with various physicochemical properties by chemical modification or doping. Recently, copper selenide nanomaterials have shown unique properties such as LSPR in the near-infrared region, making them attractive for near-infrared thermal ablation, photoacoustic imaging, disease marker detection, multimode imaging, and so on. Currently, to the best of our knowledge, there is no review on the LSPR properties of copper selenide nanomaterials and its biomedical applications. This review first discusses the relationship between the physicochemical properties and the LSPR of copper selenide nanomaterials and then summarizes the latest progress in the application of copper selenide nanomaterials in biological detection, diagnosis, and treatment of diseases. In addition, the advantages, and prospects of copper selenide nanomaterials in biomedicine are also highlighted.     

Listen to the chemical and histological information in biological tissue

Photoacoustic imaging (PAI), as an emerging biomedicine diagnostic technique that has been developed quickly in the past decade, inherits the high spatial resolution of ultrasonography in imaging deep tissue and the high sensitivity of optical imaging in evaluating tissue chemical and physiological information. In this paper, after introducing the basic principles of PAI including both photoacoustic tomography and photoacoustic microscopy, we will review some recent progress of PAI in biomedicine and demonstrate the capability of PAI in detecting the chemical compositions and in evaluating the histological microstructures in biological tissue.     

In vivo magnetic resonance detection of cancer by using multifunctional magnetic nanocrystals

The unique properties of magnetic nanocrystals provide them with high potential as key probes and vectors in the next generation of biomedical applications. Although superparamagnetic iron oxide nanocrystals have been extensively studied as excellent magnetic resonance imaging (MRI) probes for various cell trafficking, gene expression, and cancer diagnosis, further development of in vivo MRI applications has been very limited. Here, we describe in vivo diagnosis of cancer, utilizing a well-defined magnetic nanocrystal probe system with multiple capabilities, such as small size, strong magnetism, high biocompatibility, and the possession of active functionality for desired receptors. Our magnetic nanocrystals are conjugated to a cancer-targeting antibody, Herceptin, and subsequent utilization of these conjugates as MRI probes has been successfully demonstrated for the monitoring of in vivo selective targeting events of human cancer cells implanted in live mice. Further conjugation of these nanocrystal probes with fluorescent dye-labeled antibodies enables both in vitro and ex vivo optical detection of cancer as well as in vivo MRI, which are potentially applicable for an advanced multimodal detection system. Our study finds that high performance in vivo MR diagnosis of cancer is achievable by utilizing improved and multifunctional material properties of iron oxide nanocrystal probes.     

Near-infrared fluorescent molecular probes for imaging and diagnosis of nephro-urological diseases

Near-infrared (NIR) fluorescence imaging has improved imaging depth relative to conventional fluorescence imaging in the visible region, demonstrating great potential in both fundamental biomedical research and clinical practice. To improve the detection specificity, NIR fluorescence imaging probes have been under extensive development. This review summarizes the particular application of optical imaging probes with the NIR-I window (700–900 nm) or the NIR-II window (1000–1700 nm) emission for diagnosis of nephron-urological diseases. These molecular probes have enabled contrast-enhanced imaging of anatomical structures and physiological function as well as molecular imaging and early diagnosis of acute kidney injury, iatrogenic ureteral injury and bladder cancer. The design strategies of molecular probes are specifically elaborated along with representative imaging applications. The potential challenges and perspectives in this field are also discussed.

Near-infrared fluorescent molecular probes with improved imaging depth and optimized biodistribution have been reviewed, showing great potential for diagnosis of nephro-urological diseases.     

单分子定位超分辨显微成像有机荧光探针的研究进展

在生物医学领域,对纳米尺寸级别的微小生物目标进行精确定位研究具有非常重要的意义,而光学显微成像技术为此提供了强有力的工具。 光学显微成像技术受到光学衍射极限的限制,难以分辨尺寸在衍射极限(<200 nm)以下的生物结构,无法直接获取微小生物结构信息,阻碍了生物医学的进一步发展。 近年来,随着纳米分辨显微成像技术的出现,新型荧光探针的开发、成像系统与设备的不断发展及成像算法不断完善地深入结合,促进了光学衍射极限以下尺寸微观目标的研究。 基于单分子定位的超分辨荧光显微成像(SMLM)包括光激活定位成像(PALM)与随机光学重构超分辨成像(STORM),将有机荧光探针与超分辨光学显微成像技术紧密结合在一起,荧光探针的光物理性质直接决定着超分辨成像结果的好坏。 因此,设计不同性能的荧光探针可以实现超精细结构的不同超分辨成像,为研究其生物学功能提供了有力的工具。 本文着重围绕基于SMLM的原理、有机荧光探针的设计要求、用于SMLM的荧光探针种类及其生物应用等方面进行总结综述,指出了单分子定位成像上存在的不足,并对其发展方向进行了展望,希望为对超分辨成像研究感兴趣或初涉该领域的研究者提供成像理论与探针设计方面的帮助。     

Near-infrared quantum dots for deep tissue imaging

Developments in nanotechnology have paved the way for the early detection, treatment, and prevention of several tumors which affect mankind. In the past few years, near-infrared (NIR) fluorescence imaging techniques have emerged that enable the in vivo imaging of physiological, metabolic, and molecular function. The NIR window, also known as the diagnostic window (700–900 nm), can be explored for sensitive detection techniques. Nanoparticles, particularly semiconductor quantum dots (QDs), can be utilized for the purpose of optical imaging. These semiconductor QDs possess novel electronic, optical, magnetic, and structural properties which are quite different from those of bulk materials. NIR QDs with these unique properties can be utilized as contrast agents for optical imaging, particularly for deep tissue imaging. Deep tissue imaging provides more information about the pathological status of the disease, which makes the treatment more effective and efficient. In this review we highlight the importance of NIR QDs as probes for optical imaging. We describe the different types of NIR QDs, their synthesis, and their application for deep tissue imaging along with recently developed self-illuminating NIR QDs.     

Polyfluorene based conjugated polymer nanoparticles for two-photon live cell imaging

Two-photon excitation microscopy (2PEM) has been known as a noninvasive and powerful bio-imaging tool for studying living cells, intact tissues and living animals because of their unique advantages such as localized excitation, deep tissue penetration as well as less photo-damage. However, the major limitations that hinder its practical applications in biological systems are low two-photon absorption cross sections of conventional fluorescence probes. Conjugated polymer nanoparticles (CPNs) consisting of highly fluorescent conjugated polymers are promising fluorescent probes for 2PEM due to their unique advantages including large two-photon absorption cross sections, high fluorescence quantum yield, good photo-stability and biocompatibility, facile chemical synthesis, tunable optical properties as well as versatile surface modifications. This account summarizes the recent efforts of our group on development of novel polyfluorene based CPNs as 2PEM contrast agents for live cell imaging.