可激活磁共振成像纳米探针的制备及生物医学应用

在生物医学领域,磁共振成像是一种非常重要的疾病诊疗技术.近50%的磁共振检查已经涉及造影剂的应用.可激活磁共振成像纳米探针以优化信噪比为原则,借助特异性的生物分子识别作用或分子交互作用增强磁共振信号,提高了磁共振诊断的敏感性与特异性,推动着磁共振成像在生物医学领域的广泛应用.本文就目前国内外热门研究的可激活磁共振纳米探针的种类、原理等方面进行阐述,详细介绍了可激活磁共振纳米探针在生物医学上的应用,在前景方面也进行了展望.     

近红外二区有机小分子荧光探针

荧光成像凭借灵敏度高、特异性强等诸多优势在重大疾病的诊疗领域发挥着重要作用.然而传统的近红外一区（NIR-I,700~900 nm）荧光成像存在组织穿透性差等问题,限制了其临床应用.近红外二区（NIR-II,1000~1700 nm）荧光成像可以极大地减弱生物组织对光的吸收、散射和自发荧光,从而显著提升成像深度及成像效果.在众多NIR-II荧光探针中,有机小分子由于具有毒性低、代谢快等优点正成为该领域的研究热点.作者以近年来NIR-II有机小分子荧光探针的发展为主体,概括了提升探针荧光量子产率的策略,分别就可激活型、多模态成像型和诊疗一体化型NIR-II荧光探针进行分类讨论,系统介绍了近年来该领域内的研究成果,并针对NIR-II荧光探针未来的发展进行了展望.     

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。     

钆类造影剂用于肿瘤靶向性成像

核磁共振成像(MRI)是肿瘤诊断的重要手段,特别是各种造影剂的使用加速了临床应用范围.目前临床MRI检查所用各类造影剂如Gd-DTPA-BMA、Gd-DOTA等均为小分子造影剂,存在组织特异性低、体内停留时间短等缺点.构建具有组织特异性的新一代高效、低毒MRI造影剂成为材料界、医学界的研究热点之一.本文在综合最新文献的...     

金属配位化合物在生物分析、成像以及染色方面的应用

由于优越的光物理和光化学特性,很多金属配合物长期以来被用于生物传感器、生物探针和医学诊断等领域。本文综述了近年来已经或有望成功应用于生命科学基础研究和临床医学诊断众多领域中的多种金属配位化合物,包括几种在成功商业化的体外诊断系统中作为分子探针、生物标记物或蛋白染色剂而广泛应用的金属钌配位化合物和稀土金属配位化合物,在核磁共振成像技术中作为造影剂或影像增强剂的系列金属钆配位化合物,以及在细胞成像、生物标记和蛋白质分析应用中极具商业化应用前景的一些新型环金属铱配位化合物等。此外,本文还对金属配合物结合纳米结构及技术在生物医学领域中的应用作了简单介绍和展望。     

半导体共轭聚合物光学探针的设计及在自发光成像和光声成像中的应用

光学成像因其无侵袭性、高时空分辨率和高灵敏度在生物医学领域得到迅速发展.光学成像中自发光成像包括化学发光成像和长余辉成像不需实时光激发,避免了自发荧光的影响,可以得到较高的灵敏度和信噪比.光声成像则是将光信号通过热膨胀转化为声信号,避免了光散射的影响,具有较高的组织穿透深度.本文针对半导体共轭聚合物光学探针在自发光成像和光声成像技术中的应用进行综述,重点介绍了半导体共轭聚合物光学探针用于增强自发光成像、光声成像的信号强度的设计策略,以及响应型光声探针的设计原理.阐述了通过降低光学探针与发光底物之间的能隙等策略增强自发光成像信号强度,通过淬灭荧光或加速热扩散等策略放大光声信号,以及通过特异性生物分子识别或相互作用激活的响应型光声探针的具体研究成果.最后,对半导体共轭聚合物光学探针在光学成像领域存在的挑战和前景进行了展望.     

肿瘤特异性多肽探针及其在生物成像中的应用

肿瘤是由细胞、细胞外基质及微环境等多因素组成的复杂系统,不同因素在肿瘤的发生和发展中发挥关键作用.肿瘤细胞、细胞外基质及微环境的特异性分析对于肿瘤的精准诊断和靶向治疗至关重要.多肽探针具有特异性高、生物相容性好、组织穿透能力强和易于制备等优点,已被广泛用于肿瘤的特异性成像研究.本文综述了多肽探针对肿瘤细胞、免疫细胞等细胞靶点的特异性成像;并介绍了以胶原蛋白、纤维蛋白等外基质蛋白为靶点的肿瘤特异性多肽探针的成像研究.本文还总结了对肿瘤微环境中弱酸性、高酶活性等因素响应的肿瘤特异性多肽探针及其生物成像应用.最后,本文总结并讨论了肿瘤特异性多肽探针所面临的挑战与机遇,展望了其在肿瘤精准诊断和个性化治疗领域的前景.     

多功能超声造影剂

与其他成像方法相比,超声成像具有成像效果好、实时成像、操作简便、无放射性污染、价格相对低廉、适用面广以及适用于床旁等诸多无法比拟的优点,因此是目前临床上应用最为广泛的成像诊断手段之一。临床上使用超声造影剂可以提高疾病诊断的准确性,但是,超声成像自身的缺点如灵敏度相对较低等使其在对癌症等重大疾病进行诊断时存在一定的局限性。将超声成像与其他成像模式联合使用则可实现优势互补,为临床诊断提供更快捷、更精确和更清晰的图像,为疾病的诊治提供更多的信息。同时,由于超声成像实时便捷的特性,使得超声成像特别适合与多种治疗方式结合在一起,开发超声成像实时监控治疗的复合试剂,即基于超声成像的诊断治疗一体化试剂。本文介绍了以超声成像为核心的多功能造影剂,包括靶向超声造影剂、多模态造影剂以及基于超声成像的诊断治疗一体化试剂,综述了近年来有关这一研究热点的报道,并提出了存在的问题以及今后可能的研究方向。     

整合荧光成像和化疗的有机小分子诊疗探针的研究进展

将诊断与治疗功能结合为一体是当前应对癌症的一种新兴策略. 诊疗一体化作为一种潜在的新型医学诊治方式, 在快速获得体内信息、 改善生物分布、 减少剂量和降低毒副作用等方面具有潜在的应用前景. 荧光成像被广泛应用于医学诊断, 近年来近红外荧光成像技术得到飞速发展, 在活体成像方面具有较好的穿透深度和成像分辨率. 本文综合评述了部分整合荧光成像和化疗的有机单分子诊疗试剂的相关研究, 并对诊疗一体化探针的未来研究进行了展望.     

自组装多肽探针在磁共振成像中的应用

磁共振成像(MRI)是一种强大的非侵入式生物医学诊断技术. 临床上, MRI需要借助造影剂来提高成像质量, 从而提高诊断的准确性. 由于具有优越的信号放大能力和生物相容性, 自组装多肽探针可负载特定的MRI分子, 通过酶促自组装过程实现肿瘤靶向和特异性富集, 增强肿瘤病灶区MRI信号, 从而进一步提高MRI的准确性和灵敏度. 本综述总结了近年来多肽自组装探针在不同MRI模式( ¹H MRI, ¹⁹F MRI和双自旋核MRI)下的最新进展, 并展望了这类新型探针在MRI领域的应用前景.     

In situ Activatable Peptide-based Nanoprobes for Tumor Imaging

Owing to its excellent biological properties, peptide has been widely used in the design of nanoprobes capable of enhancing tumor imaging signals. In recent years, a number of peptide-based nanoprobes with strong loading capacity and great biocompatibility have been developed for precision tumor imaging by coupling peptide motifs with different imaging agents. It is worth noting that, compared with "always on" mode, the use of stimulus-mediated in situ activatable mode to design and control the self-assembly or nanostructure transformation of peptide-based nanoprobes in vivo can achieve the significant improvement of imaging efficiency. Herein, we summarize the recent progress of in situ activatable peptide-based nanoprobes for tumor imaging in diverse imaging modes, including magnetic resonance imaging(MRI), fluorescence imaging(FI), photoacoustic imaging(PAI), radionuclide imaging(RI) and multimodal imaging. Finally, we briefly prospect the challenges and potential development directions of this field.     

Activatable fluorescence sensors for in vivo bio-detection in the second near-infrared window

Fluorescence imaging in the second near-infrared (NIR-II, 1000–1700 nm) window has exhibited advantages of high optical resolution at deeper penetration (ca. 5–20 mm) in bio-tissues owing to the reduced photon scattering, absorption and tissue autofluorescence. However, the non-responsive and “always on” sensors lack the ability of selective imaging of lesion areas, leading to the low signal-to-background ratio (SBR) and poor sensitivity during bio-detection. In contrast, activatable sensors show signal variation in fluorescence intensity, spectral wavelength and fluorescence lifetime after responding to the micro-environment stimuli, leading to the high detection sensitivity and reliability in bio-sensing. This minireview summarizes the design and detection ability of recently reported NIR-II activatable sensors. Furthermore, the challenges, opportunities and prospects of NIR-II activatable bio-sensing are also discussed.

Fluorescence imaging in the second near-infrared (NIR-II, 1000–1700 nm) window has exhibited advantages of high optical resolution at deeper penetration (ca. 5–20 mm) in bio-tissues owing to the reduced photon scattering and tissue autofluorescence.     

Maltohexaose-based probes for bacteria-specific imaging:Great sensitivity,specificity and translational potential

Infectious diseases have always been a major cause of mobility and mortality,early and accurate diagnosis is important for their management.However,current clinical diagnosis for bacterial infection still remains troublesome.Recently,many attempts on molecular imaging have been made for prompt bacteria detection,especially for early and precise disease diagnosis.Among them,maltohexaose-based probes serve as a superb candidate due to the bacteria-specific maltodextrin transport pathway.These probes can visualize bacterial foci with unparalleled sensitivity and specificity.Such metabolism-based targeting strategy offers a powerful delivery platform for imaging and theranostic agents,providing good translational potential for developing antibacterial agents.     

Imaging of Colorectal Cancers Using Activatable Nanoprobes with Second Near‐Infrared Window Emission

Fluorescent probes in the second near‐infrared window (NIR‐II) allow high‐resolution bioimaging with deep‐tissue penetration. However, existing NIR‐II materials often have poor signal‐to‐background ratios because of the lack of target specificity. Herein, an activatable NIR‐II nanoprobe for visualizing colorectal cancers was devised. This designed probe displays H₂S‐activated ratiometric fluorescence and light‐up NIR‐II emission at 900–1300 nm. By using this activatable and target specific probe for deep‐tissue imaging of H₂S‐rich colon cancer cells, accurate identification of colorectal tumors in animal models were performed. It is anticipated that the development of activatable NIR‐II probes will find widespread applications in biological and clinical systems.     

Spatially Resolved Quantification of Gadolinium(III)‐Based Magnetic Resonance Agents in Tissue by MALDI Imaging Mass Spectrometry after In Vivo MRI

Gadolinium(III)‐based contrast agents improve the sensitivity and specificity of magnetic resonance imaging (MRI), especially when targeted contrast agents are applied. Because of nonlinear correlation between the contrast agent concentration in tissue and the MRI signal obtained in vivo, quantification of certain biological or pathophysiological processes by MRI remains a challenge. Up to now, no technology has been able to provide a spatially resolved quantification of MRI agents directly within the tissue, which would allow a more precise verification of in vivo imaging results. MALDI imaging mass spectrometry for spatially resolved in situ quantification of gadolinium(III) agents, in correlation to in vivo MRI, were evaluated. Enhanced kinetics of Gadofluorine M were determined dynamically over time in a mouse model of myocardial infarction. MALDI imaging was able to corroborate the in vivo imaging MRI signals and enabled in situ quantification of the gadolinium probe with high spatial resolution.     

Multilayered Activatable Nanoprobe for Ultra‐Bright Tumor Imaging

The development of tumor targeted probes with strong signal and high contrast is always challenging in cancer imaging. Here, a unique multilayered activatable nanoprobe (MAN) is prepared to fulfill this long‐standing goal. MAN adopts a versatile layer‐by‐layer fabrication technique that sequentially assembles multifunctional polyelectrolytes onto nanoparticles via charge‐charge interaction. Unlike the common one‐probe‐one‐fluorochrome construct, MAN offers a dramatic fluorescence enhancement by transporting a large quantity of quenched fluorochromes for maximal signal and contrast. Excellent signal amplification and retention with negligible cytotoxicity is observed in cell study. Upon systemic injection into mice, MAN quickly accumulates in tumor and its fluorescent signal is turned on by proteases overexpressed in tumors, resulting in >700% tumor‐to‐normal‐tissue contrast. This multilayered fabrication provides a simple and powerful universal platform to design sensitive tumor imaging probes.     

pH响应型近红外菁类荧光探针的合成及细胞成像

癌症的早期诊治是提高癌症患者治愈率的关键。但传统的"always on"型显影剂存在自身背景干扰且易造成"假阳性"等问题。本文利用肿瘤细胞具有弱酸性这一特性,设计合成了p H激活型不对称菁类荧光探针,并选用氨基葡萄糖作为修饰基团以增强探针母体的水溶性并赋予其肿瘤靶向性。该探针具有p H调控的"off-on"可逆的近红外荧光特性,以及与肿瘤弱酸性微环境相吻合的p H响应范围。此外,探针的浓度高达1.0×10~(-5)mol/L时仍未表现出明显的细胞毒性。该探针在细胞水平实现了肿瘤细胞弱酸性微环境的特异性成像。     

磁共振/光学双模态分子探针的研究现状与展望

基于磁共振与荧光成像的双模态成像技术不仅克服了传统单一分子影像技术在灵敏度、特异度、分辨率等方面的固有缺陷，更是拓宽了分子影像技术在诊断及治疗监控等领域的研究范围及应用前景。本文将对磁共振/荧光双模态分子探针的应用情况和研究进展等进行综述。     

A pH-Sensitive Zwitterionic Iron Complex Probe with High Biocompatibility for Tumor-Specific Magnetic Resonance Imaging

Accurate diagnosis of tumor characteristics, including its location and boundary, is of immense value to subsequent therapy. Activatable magnetic resonance imaging (MRI) contrast agents that respond to tumor-specific microenvironments, such as the redox state, pH, and enzyme activity, enable better mapping of tumor tissue. However, the practical application of most reported activatable agents is hampered by problems including potential toxicity, inefficient elimination, and slow activation. In this study, we developed a zwitterionic iron complex (Fe-ZDS) as a positive MRI contrast agent for tumor-specific imaging. Fe-ZDS could dissociate in weakly acidic solution rapidly, accompanied by clear longitudinal relaxivity (r₁) enhancement, which enabled the complex to act as a pH-sensitive contrast agent for tumor-specific MR imaging. In vivo experiments showed that Fe-ZDS rapidly enhanced the tumor-to-normal contrast ratio by >40 %, which assisted in distinguishing the tumor boundary. Furthermore, Fe-ZDS circulated freely in the bloodstream and was excreted relatively safely via kidneys owing to its zwitterionic nature. Therefore, Fe-ZDS is an ideal candidate for a tumor-specific MRI contrast agent and holds considerable potential for clinical translation.     

An Activatable Polymeric Reporter for Near-Infrared Fluorescent and Photoacoustic Imaging of Invasive Cancer

Discriminative detection of invasive and noninvasive breast cancers is crucial for their effective treatment and prognosis. However, activatable probes able to do so in vivo are rare. Herein, we report an activatable polymeric reporter (P-Dex) that specifically turns on near-infrared (NIR) fluorescent and photoacoustic (PA) signals in response to the urokinase-type plasminogen activator (uPA) overexpressed in invasive breast cancer. P-Dex has a renal-clearable dextran backbone that is linked with a NIR dye caged with an uPA-cleavable peptide substrate. Such a molecular design allows P-Dex to passively target tumors, activate NIR fluorescence and PA signals to effectively distinguish invasive MDA-MB-231 breast cancer from noninvasive MCF-7 breast cancer, and ultimately undergo renal clearance to minimize the toxicity potential. Thus, this polymeric reporter holds great promise for the early detection of malignant breast cancer.