Functional tumor imaging based on inorganic nanomaterials

Inorganic nanomaterials have attracted substantial research interest due to their unique intrinsic physicochemical properties.We highlighted recent advances in the applications of inorganic nanoparticles regarding their imaging efficacy, focusing on tumor-imaging nanomaterials such as metal-based and carbon-based nanomaterials and quantum dots. Inorganic nanoparticles gain excellent in vivo tumor-imaging functions based on their specific characteristics of strong near-infrared optical absorption and/or X-ray attenuation capability. The specific response signals from these novel nanomaterials can be captured using a series of imaging techniques, i.e., optical coherence tomography(OCT), X-ray computed tomography(CT) imaging, two-photon luminescence(TPL), photoacoustic tomography(PAT), magnetic resonance imaging(MRI), surface-enhanced Raman scattering(SERS) and positron emission tomography(PET). In this review, we summarized the rapid development of inorganic nanomaterial applications using these analysis techniques and discussed the related safety issues of these materials.     

Polymeric micelles in diagnostic imaging

The results are presented describing the use of polymeric micelles for gamma, magnetic resonance (MR), and computed tomography (CT) imaging. Micelle-forming diacyllipid-PEG conjugates were loaded with monomeric and polymeric amphiphilic chelates, containing entrapped metals, such as 111-In or Gd, and used for the experimental gamma and MR imaging of lymphatics in rabbits. The method is described to prepare polymeric iodine-containing PEG-based micelles which may act as a long-circulating blood pool imaging agent for CT. Experimental CT-imaging performed in mice and rabbits demonstrated high potential of a micellar contrast agent.     

分子影像探针

分子影像是近年出现并迅速发展的一个生物医学领域,在疾病的治疗与诊断中发挥着重要作用。同时它又是一门交叉学科,涉及化学、医学、生物、计算机科学、放射科学、材料科学等。分子影像的发展除了需要先进的成像设备外,最关键的是合成新型而高效的成像探针。目前,分子影像探针广泛应用于科学研究和临床,并且也取得了巨大进步。本文主要综述了5种常见的分子影像探针:超声成像探针、X-射线计算机断层成像探针、光学成像探针、核磁共振成像探针、正电子发射计算机断层扫描成像探针,并对分子影像探针的应用进行了概述,最后对分子影像探针的发展进行了展望。     

Study of OSEM with different subsets in grating-based X-ray differential phase-contrast imaging

Impressive developments in X-ray imaging are associated with X-ray phase contrast computed tomography based on grating interferometry, a technique that provides increased contrast compared with conventional absorption-based imaging. A new "single-step" method capable of separating phase information from other contributions has been recently proposed. This approach not only simplifies data-acquisition procedures, but, compared with the existing phase step approach, significantly reduces the dose delivered to a sample. However, the image reconstruction procedure is more demanding than for traditional methods and new algorithms have to be developed to take advantage of the "single-step" method. In the work discussed in this paper, a fast iterative image reconstruction method named OSEM (ordered subsets expectation maximization) was applied to experimental data to evaluate its performance and range of applicability. The OSEM algorithm with different subsets was also characterized by comparison of reconstruction image quality and convergence speed. Computer simulations and experimental results confirm the reliability of this new algorithm for phase-contrast computed tomography applications. Compared with the traditional filtered back projection algorithm, in particular in the presence of a noisy acquisition, it furnishes better images at a higher spatial resolution and with lower noise. We emphasize that the method is highly compatible with future X-ray phase contrast imaging clinical applications.     

In situ heterodyne detection in femtosecond time resolved four wave mixing

A novel heterodyne detection technique is introduced for femtosecond time resolved four wave mixing (TRFWM). A ‘local oscillator’ field is generated in situ either by the self alignment of the molecules in the ultrashort field, or by the rotational alignment signal from a small amount of anisotropic molecules added to the sample. Like other heterodyne detection schemes, the method enables linearization of the third-order nonlinear signal and clear identification of fundamental vibrational modes and their separation from vibrational beat frequencies. However, unlike others, the method is easy to implement and does not require interferometric stability of the optical setup.     

Molecular Targeting of Epidermal Growth Factor Receptor (EGFR) and Vascular Endothelial Growth Factor Receptor (VEGFR)

Epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR) are two extensively studied membrane-bound receptor tyrosine kinase proteins that are frequently overexpressed in many cancers. As a result, these receptor families constitute attractive targets for imaging and therapeutic applications in the detection and treatment of cancer. This review explores the dynamic structure and structure-function relationships of these two growth factor receptors and their significance as it relates to theranostics of cancer, followed by some of the common inhibition modalities frequently employed to target EGFR and VEGFR, such as tyrosine kinase inhibitors (TKIs), antibodies, nanobodies, and peptides. A summary of the recent advances in molecular imaging techniques, including positron emission tomography (PET), single-photon emission computerized tomography (SPECT), computed tomography (CT), magnetic resonance imaging (MRI), and optical imaging (OI), and in particular, near-IR fluorescence imaging using tetrapyrrolic-based fluorophores, concludes this review.     

Large-scale synthesis of bioinert tantalum oxide nanoparticles for X-ray computed tomography imaging and bimodal image-guided sentinel lymph node mapping

Ever since Au nanoparticles were developed as X-ray contrast agents, researchers have actively sought alternative nanoparticle-based imaging probes that are not only inexpensive but also safe for clinical use. Herein, we demonstrate that bioinert tantalum oxide nanoparticles are suitable nanoprobes for high-performance X-ray computed tomography (CT) imaging while simultaneously being cost-effective and meeting the criteria as a biomedical platform. Uniformly sized tantalum oxide nanoparticles were prepared using a microemulsion method, and their surfaces were readily modified using various silane derivatives through simple in situ sol-gel reaction. The silane-modified surface enabled facile immobilization of functional moieties such as polyethylene glycol (PEG) and fluorescent dye. PEG was introduced to endow the nanoparticles with biocompatibility and antifouling activity, whereas immobilized fluorescent dye molecules enabled simultaneous fluorescence imaging as well as X-ray CT imaging. The resulting nanoparticles exhibited remarkable performances in the in vivo X-ray CT angiography and bimodal image-guided lymph node mapping. We also performed an extensive study on in vivo toxicity of tantalum oxide nanoparticles, revealing that the nanoparticles did not affect normal functioning of organs.     

Progress of diffraction enhanced imaging at the Beijing Synchrotron Radiation Facility

A simple framework that allows a new general diffraction enhanced imaging (DEI) equation to be derived is presented. This latter equation may explain all open problems associated with the equation introduced by Chapman and those not explained by the first DEI equation, such as the noise background due to the small-angle scattering reflected by the analyzer. Combing the DEI equation with computed tomography (CT) theory, we propose a new DEI–CT formula that explains qualitatively the contour contrast caused by extinction of the refraction. Two formulae with a new method to extract the refraction angle are also introduced. Within this new theoretical framework the three components of the gradient of the refractive index can be reconstructed.     

氟硼二吡咯探针在肿瘤检测中的应用

目前,肿瘤是世界上死亡率最高的疾病之一,早期肿瘤细胞的检测对于肿瘤的预防和治疗具有重要意义。当前针对肿瘤细胞的检测手段主要有X光、计算机断层扫描(CT)、磁共振成像(MRI)等,但借助这些手段检测出来的肿瘤细胞通常已生长到中后期,极不利于肿瘤的治疗。荧光成像作为生命科学研究领域常用的手段之一,近年来被用于肿瘤细胞检测,与其他检测方法相比,具有微创、高效、低成本和更加灵敏等优势。氟硼二吡咯(BODIPY)荧光染料作为荧光成像的工具之一,因具有荧光量子产率高、稳定性好、易于修饰等独特优势,被广泛应用于肿瘤细胞检测领域。与常规检测手段相比,BODIPY探针可以靶向肿瘤细胞内细胞器或肿瘤标志物,达到检测早期肿瘤细胞的目的。本文综述了靶向不同标记分子的BODIPY探针的应用,并分析了BODIPY探针的作用机理,以期为肿瘤的临床检测提供更加方便、快捷、直观、灵敏的工具。     

Quantitative analysis in medicine using photoacoustic tomography

Photoacoustic imaging, or photoacoustic tomography, is a 2D or 3D optical imaging method based on localized optical absorption of pulsed laser radiation. By a spatially resolved detection of the following thermoelastic expansion, the local distribution of the absorption can be determined. The technique has been proven to have significant potential for the imaging of human and animal organs and single blood vessels, combining high contrast with good spatial resolution. The contrast is based on the specific optical absorption of certain components in the visible and near-infrared spectral range, for most applications of blood. Generally, the images represent the local distribution of blood in a qualitative or semiquantitative way. Although photoacoustic imaging is capable of revealing absolute and spatially resolved concentrations of endogenous (such as oxyhemoglobin and deoxyhemoglobin) or artificial (such as tumor markers) chromophores, only a very limited number of publications have dealt with this demanding task. In this report, the problems involved and possible solutions are reviewed and summarized.     

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.     

Antibiofouling polymer-coated gold nanoparticles as a contrast agent for in vivo X-ray computed tomography imaging

Current computed tomography (CT) contrast agents such as iodine-based compounds have several limitations, including short imaging times due to rapid renal clearance, renal toxicity, and vascular permeation. Here, we describe a new CT contrast agent based on gold nanoparticles (GNPs) that overcomes these limitations. Because gold has a higher atomic number and X-ray absorption coefficient than iodine, we expected that GNPs can be used as CT contrast agents. We prepared uniform GNPs ( approximately 30 nm in diameter) by general reduction of HAuCl4 by boiling with sodium citrate. The resulting GNPs were coated with polyethylene glycol (PEG) to impart antibiofouling properties, which extends their lifetime in the bloodstream. Measurement of the X-ray absorption coefficient in vitro revealed that the attenuation of PEG-coated GNPs is 5.7 times higher than that of the current iodine-based CT contrast agent, Ultravist. Furthermore, when injected intravenously into rats, the PEG-coated GNPs had a much longer blood circulation time (>4 h) than Ultravist (<10 min). Consequently, CT images of rats using PEG-coated GNPs showed a clear delineation of cardiac ventricles and great vessels. On the other hand, relatively high levels of GNPs accumulated in the spleen and liver, which contain phagocytic cells. Intravenous injection of PEG-coated GNPs into hepatoma-bearing rats resulted in a high contrast ( approximately 2-fold) between hepatoma and normal liver tissue on CT images. These results suggest that PEG-coated GNPs can be useful as a CT contrast agent for a blood pool and hepatoma imaging.     

Sensitive and selective tumor imaging with novel and highly activatable fluorescence probes.

Selective and sensitive tumor imaging in vivo is one of the most requested methodologies in medical sciences. Although several imaging modalities have been developed including positron emission tomography (PET) and magnetic resonance (MR) imaging for the detection of tumors, none of these modalities can activate the signals upon being accumulated or uptaken to tumor sites. Among these modalities, only optical fluorescence imaging has a marked advantage, that is, their signals can be dramatically increased upon detecting some biological features. In this short review, I will introduce some recent strategies for activatable optical fluorescence imaging of tumors, and discuss their advantages over other modalities.     

Engineering of lipid-coated PLGA nanoparticles with a tunable payload of diagnostically active nanocrystals for medical imaging

Polylactic-co-glycolic acid (PLGA) based nanoparticles are biocompatible and biodegradable and therefore have been extensively investigated as therapeutic carriers. Here, we engineered diagnostically active PLGA nanoparticles that incorporate high payloads of nanocrystals into their core for tunable bioimaging features. We accomplished this through esterification reactions of PLGA to generate polymers modified with nanocrystals. The PLGA nanoparticles formed from modified PLGA polymers that were functionalized with either gold nanocrystals or quantum dots exhibited favorable features for computed tomography and optical imaging, respectively.     

Design and preliminary assessment of 99mTc-labeled ultrasmall superparamagnetic iron oxide-conjugated bevacizumab for single photon emission computed tomography/magnetic resonance imaging of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) has a very high incidence and mortality. Early diagnosis and timely treatments are therefore required to improve the quality of life and survival rate of HCC patients. Here, we developed a vascular endothelial growth factor (VEGF)-based multimodality imaging agent for single photon emission computed tomography (SPECT), computed tomography (CT) and magnetic resonance imaging (MRI) and used it to assess HCC mice and explore the combinative value of CT/MRI-based morphological imaging and SPECT functional imaging. HCC targeting with ¹²⁵I-labeled bevacizumab monoclonal antibody (mAb) was examined using SPECT/CT in HepG2 tumor-bearing mice after intravenous mAb injection. Based on this, an integrated, bimodal, VEGF-targeted, ultrasmall superparamagnetic iron oxide (USPIO)-conjugated ^99mTc-labeled bevacizumab mAb was synthesized to increase tumor penetration and accumulations. The in vivo pharmacokinetics and HepG2 tumor targeting were explored through in vivo planar imaging and SPECT/CT using a mouse model of HepG2 liver cancer. The specificity of the radiolabeled nanoparticles for HepG2 HCC was verified using in vitro immunohistochemistry and Prussian blue staining. With diethylenetriamine pentaacetic acid as a bifunctional chelating agent, USPIO-bevacizumab achieved a ^99mTc labeling efficiency of >90 %. The in vivo imaging results also exhibited the targeting of USPIO on HepG2 HCC. The specificity of these results was confirmed using in vitro immunohistochemistry and Prussian blue staining. Our preliminary findings showed the potential of USPIO as an imaging agent for the SPECT/MRI of HepG2 HCC.     

Solute-solvent halogen bonding during adsorption on silver nanostructures

Multimodal imaging technique is an alternative approach to improve sensitivity of early cancer diagnosis. In this study, highly fluorescent and strong X-ray absorption coefficient gold nanoclusters (Au NCs) are synthesized as dual-modality imaging contrast agents (CAs) for fluorescent and X-ray dual-modality imaging. The experimental results show that the as-prepared Au NCs are well constructed with ultrasmall sizes, reliable fluorescent emission, high computed tomography (CT) value and fine biocompatibility. In vivo imaging results indicate that the obtained Au NCs are capable of fluorescent and X-ray enhanced imaging.     

PEGylated WS2 nanosheets for X-ray computed tomography imaging and photothermal therapy

WS2 nanosheets were prepared by the solvent-thermal method in the presence of n-butyl lithium, then the exfoliation under the condition of ultrasound. The formed WS2 nanosheets were conjugated with thiol-modified polyethylene glycol (PEG-SH) to improve the biocompatibility. The nanosheets (WS2-PEG) were able to inhibit the growth of a model HeLa cancer cell line in vitro due to the high photothermal conversion efficiency of 35% irradiated by an 808 nm laser (1 W/cm2). As a proof of concept, WS2-PEG nanosheets with the better X-ray attenuation property than the clinical computed tomography (CT) contrast agent (Iohexol) could be performed for CT imaging of the lymph vessel.     

Detection of stress whitening in plastics with the help of X-ray dark field imaging

The processing of thermoplastics can induce a wide range of defects such as stress whitening, cavitation and porosity, which can adversely affect the reliability of the final products. Hence, fast and effective non-destructive detection methods for such defects are highly important for quality assurance on production lines. In this paper, X-ray dark field imaging is presented as a new non-destructive testing method that allows the visualization of stress whitening or cavitation efficiently. The performance of the method is demonstrated for the case of an injection-moulded polyvinylidene fluoride part that exhibits stress whitening. Whereas the stress whitening could not be detected by conventional X-ray imaging, it was localized by an X-ray dark field image acquired within a few minutes. Once the precise location of the stress whitening was known, it was possible to verify the result by local micro X-ray computed tomography and by a micro section image.     

Emerging applications of near-infrared fluorescent metal nanoclusters for biological imaging

Recent advances in the development of near-infrared fluorescent metal nanoclusters for bioimaging applications have been thoroughly overviewed.     

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。