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.     

New frontiers of diagnostic radiology

There have been many new imaging techniques being developed for the assessment of the various organs and their diseases. In the near future, magnetic resource imaging (MRI) will become one of the most important modalities in the evaluation of the disease processes, while computer tomography (CT), nuclear medicine, ultrasonography and other diagnostic techniques may become complementary to MRI. In any event the new techniques under development will be refined to non-invasive, less costly, easy to perform methods with higher diagnostic accuracy. In the next 10 years, these new modalities will be used more widely in clinical imaging.     

Synthesis, binding affinity, and relaxivity of target-specific MRI contrast agents

Although magnetic resonance imaging (MRI) is one of the most important imaging modalities of the central nervous system (CNS), one of the main drawbacks of MRI is its limited specificity. This can potentially be partially alleviated by target-specific contrast agents. In the present paper we describe a simple high yield synthesis of two such gadolinium-based spiperone targeted MRI contrast agents, 1a and 1b. The R₁ relaxivities of 1a and 1b were evaluated and found to be 5.94 and 8.31 mM⁻¹ s⁻¹, respectively at 9.4T, while their R₂ relaxivities at the same magnetic field were found to be 18.05 and 22.60 mM⁻¹ s⁻¹, respectively. In addition and very importantly compound 1a, which is a gadolinium-based, spiperone-targeted MRI contrast agent, was found to preserve some of the spiperone affinity toward the dopamine D2 receptor. Compounds 1a and 1b thus represent potential agents for in vitro dopamine receptor imaging using MRI in experimental models. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Apoptosis imaging by radionuclide probes

Apoptosis has attracted more and more research interests due to the critical role it played in the human health. Also, it is often confused with other types of cell death. Thus, methods that enable sensitive detection and noninvasive visualized imaging of apoptosis will be of enormous benefit in the development of new diagnostics, therapies and patient management. During the past decades, with the development of apoptosis understanding and molecular imaging modalities, a large collection of imaging agents based on well-defined molecular markers and/or physiological features have been developed and tested in preclinical and clinical studies. In this review, we mainly discuss radionuclide imaging probes, ranging from simple attachments of reporter moieties to proteins and peptides, to rationally designed probes that allow multimodal imaging. Furthermore, we briefly outline the current status of clinical translation and attempt to give an outlook on the further study.     

High-Field MRI Contrast Agents and their Synergy with Optical Imaging: the Evolution from Single Molecule Probes towards Nano-architectures

Contrast agents for magnetic resonance imaging have historically been based on paramagnetic metal complexes, particularly Gd³⁺ chelates, which tend to lose their contrast enhancement ability with increasing magnetic field strength. Emerging high-field MRI applications require the development of novel contrast agents that exhibit high relaxation enhancement as a function of magnetic field strength. Paramagnetic ions such as Dy³⁺, Tb³⁺ or Ho³⁺ incorporated into supramolecular or inorganic nano-architectures represent promising platforms for the development of high field MRI contrast agents. Furthermore, such platforms allow facile inclusion of multiple imaging modalities, therapeutic loading, and targeting vectors. This Minireview examines the application of contrast agents for high-field MRI, which range from single molecules to nanoparticles. Approaches to create multimodal agents by combining high-field MRI contrast properties with another imaging modality are also discussed.     

Lanthanide-Based Probes for Imaging Detection of Enzyme Activities by NIR Luminescence,T1- and ParaCEST MRI

Applying a single molecular probe to monitor enzymatic activities in multiple, complementary imaging modalities is highly desirable to ascertain detection and to avoid the complexity associated with the use of agents of different chemical entities. We demonstrate here the versatility of lanthanide (Ln³⁺) complexes with respect to their optical and magnetic properties and their potential for enzymatic detection in NIR luminescence, CEST and T1 MR imaging, controlled by the nature of the Ln³⁺ ion, while using a unique chelator. Based on X-ray structural, photophysical, and solution NMR investigations of a family of Ln³⁺ DO3A-pyridine model complexes, we could rationalize the luminescence (Eu³⁺, Yb³⁺), CEST (Yb³⁺) and relaxation (Gd³⁺) properties and their variations between carbamate and amine derivatives. This allowed the design of $$ probes which undergo enzyme-mediated changes detectable in NIR luminescence, CEST and T1-weighted MRI, respectively governed by variations in their absorption energy, in their exchanging proton pool and in their size, thus relaxation efficacy. We demonstrate that these properties can be exploited for the visualization of β-galactosidase activity in phantom samples by different imaging modalities: NIR optical imaging, CEST and T1-weighted MRI.     

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.     

Towards highly efficient,intelligent and bimodal imaging probes: Novel approaches provided by lanthanide coordination chemistry

Gd³⁺ complexes are widely used as contrast enhancing agents in medical magnetic resonance imaging (MRI). In recent years, new fields have emerged in their development. The general tendency of using higher magnetic fields in biomedical and clinical MRI for a better signal to noise ratio calls for new contrast agents specifically optimized for such high field applications. Molecular imaging, aiming at the non-invasive visualisation of expression and function of bioactive molecules, requires imaging probes that provide a specific magnetic response to a particular molecular event. Finally, bimodal imaging may allow for combining the excellent resolution of MRI with a good sensitivity of other imaging modalities, such as optical methods. It requires bimodal imaging probes that satisfy requirements for both modalities within a single molecule. Here we review our latest efforts to develop novel lanthanide-based contrast agents in these specific fields and demonstrate the possibilities offered by lanthanide coordination chemistry.     

Imaging the cardiovascular system: seeing is believing.

From the basic light microscope through high-end imaging systems such as multiphoton confocal microscopy and electron microscopes, microscopy has been and will continue to be an essential tool in developing an understanding of cardiovascular development, function, and disease. In this review we briefly touch on a number of studies that illustrate the importance of these forms of microscopy in studying cardiovascular biology. We also briefly review a number of imaging modalities such as computed tomography (CT), magnetic resonance imaging (MRI), ultrasound, and positron emission tomography (PET) that, although they do not fall under the realm of microscopy, are imaging modalities that greatly complement microscopy. Finally we examine the role of proper imaging system calibration and the potential importance of calibration in understanding biological tissues, such as the cardiovascular system, that continually undergo deformation in response to strain.     

Progress in drug delivery to the central nervous system by the prodrug approach

This review describes specific strategies for targeting to the central nervous system (CNS). Systemically administered drugs can reach the brain by crossing one of two physiological barriers resistant to free diffusion of most molecules from blood to CNS: the endothelial blood-brain barrier or the epithelial blood-cerebrospinal fluid barrier. These tissues constitute both transport and enzymatic barriers. The most common strategy for designing effective prodrugs relies on the increase of parent drug lipophilicity. However, increasing lipophilicity without a concomitant increase in rate and selectivity of prodrug bioconversion in the brain will result in failure. In these regards, consideration of the enzymes present in brain tissue and in the barriers is essential for a successful approach. Nasal administration of lipophilic prodrugs can be a promising alternative non-invasive route to improve brain targeting of the parent drugs due to fast absorption and rapid onset of drug action. The carrier-mediated absorption of drugs and prodrugs across epithelial and endothelial barriers is emerging as another novel trend in biotherapeutics. Several specific transporters have been identified in boundary tissues between blood and CNS compartments. Some of them are involved in the active supply of nutrients and have been used to explore prodrug approaches with improved brain delivery. The feasibility of CNS uptake of appropriately designed prodrugs via these transporters is described in detail.     

Development of nitroxide‐based theranostic compounds that act both as anti‐inflammatory drugs and brain redox imaging probes in MRI

Theranostic probes provide both therapeutic and diagnostic imaging capabilities in one molecule and show significant promise for use in magnetic resonance imaging (MRI) examinations. The present study describes for the first time the synthesis and utility of nitroxide‐based contrast agents exhibiting a nonsteroidal anti‐inflammatory drug effect. The target theranostic probes were prepared by connecting the carboxyl group of ibuprofen or ketoprofen to the hydroxyl group of 3‐hydroxymethyl‐2,2,5,5‐tetramethylprrolidine‐1‐oxyl by a condensation reaction in the presence of dicyclohexylcarbodiimide and 4‐dimethylaminopyridine in dichloromethane. MRI of mouse heads after administration of either synthesized theranostic probe indicated that the probes enter the brain by passing through the blood–brain barrier (BBB), resulting in T1 contrast enhancement in mouse brain. This enhancement persisted for the duration of the half‐life of about 40 min, which is longer than that obtained by most of pyrrolidine nitroxide molecules. The therapeutic capacities of these theranostic probes were examined using a lipopolysaccharide (LPS)‐induced brain inflammation model. The production of nitric oxide, an inflammation marker in septic mouse brain induced by LPS, was remarkably inhibited by the addition of either synthesized probe, indicating that they also act as anti‐inflammatory drugs. The present results indicate that nitroxide‐based theranostic probes act as both BBB‐permeable redox‐sensitive contrast agents and as an anti‐inflammatory drug in septic mouse brain. Copyright © 2016 John Wiley & Sons, Ltd.     

N-Aryl Amides as Chemical Exchange Saturation Transfer Magnetic Resonance Imaging Contrast Agents

Chemical exchange saturation transfer (CEST) MRI has recently emerged as a versatile molecular imaging approach in which diamagnetic compounds can be utilized to generate an MRI signal. To expand the scope of CEST MRI applications, herein, we systematically investigated the CEST properties of N-aryl amides with different N-aromatic substitution, revealing their chemical shifts (4.6–5.8 ppm) and exchange rates (up to thousands s⁻¹) are favorable to be used as CEST agents as compared to alkyl amides. As the first proof-of-concept study, we used CEST MRI to detect the enzymatic metabolism of the drug acebutolol directly by its intrinsic CEST signal without any chemical labeling. Our study implies that N-aryl amides may enable the label-free CEST MRI detection of the metabolism of many N-aryl amide-containing drugs and a variety of enzymes that act on N-aryl amides, greatly expanding the scope of CEST MR molecular imaging.     

Distribution of lipids in human brain

The enormous abundance of lipid molecules in the central nervous system (CNS) suggests that their role is not limited to be structural and energetic components of cells. Over the last decades, some lipids in the CNS have been identified as intracellular signalers, while others are known to act as neuromodulators of neurotransmission through binding to specific receptors. Neurotransmitters of lipidic nature, currently known as neurolipids, are synthesized during the metabolism of phospholipid precursors present in cell membranes. Therefore, the anatomical identification of each of the different lipid species in human CNS by imaging mass spectrometry (IMS), in association with other biochemical techniques with spatial resolution, can increase our knowledge on the precise metabolic routes that synthesize these neurolipids and their localization. The present study shows the lipid distribution obtained by MALDI-TOF IMS in human frontal cortex, hippocampus, and striatal area, together with functional autoradiography of cannabinoid and LPA receptors. The combined application of these methods to postmortem human brain samples may be envisioned as critical to further understand neurological diseases, in general, and particularly, the neurodegeneration that accompanies Alzheimer’s disease.     

Simultaneous quantification of ondansetron and tariquidar in rat and human plasma using a high performance liquid chromatography‐ultraviolet method

Ondansetron, a widely used antiemetic agent, is a P‐glycoprotein (P‐gp) substrate and therefore expression of P‐gp at the blood–brain barrier limits its distribution to the central nervous system (CNS), which was observed to be reversed by coadministration with P‐gp inhibitors. Tariquidar is a potent and selective third‐generation P‐gp inhibitor, and coadministration with ondansetron has shown improved ondansetron distribution to the CNS. There is currently no reported bioanalytical method for simultaneously quantifying ondansetron with a third‐generation P‐gp inhibitor. Therefore, we aimed to develop and validate a method for ondansetron and tariquidar in rat and human plasma samples. A full validation was performed for both ondansetron and tariquidar, and sample stability was tested under various storage conditions. To demonstrate its utility, the method was applied to a preclinical pharmacokinetic study following coadministration of ondansetron and tariquidar in rats. The presented method will be valuable in pharmacokinetic studies of ondansetron and tariquidar in which simultaneous determination may be required. In addition, this is the first report of a bioanalytical method validated for quantification of tariquidar in plasma samples.     

产前超声联合MRI对胎儿中枢神经系统畸形的筛查价值

本文对产前超声联合核磁共振成像（MRI）筛查胎儿中枢神经系统（CNS）畸形的价值进行了分析。研究对象选取2016年1月~2019年2月本院收治的疑似胎儿CNS畸形的孕妇196例,所有孕妇均给予产前超声、MRI检查,以产后结果为对照,分析产前超声、MRI及二者联合对胎儿CNS畸形的筛查价值。结果显示,产后胎儿CNS畸形84例（42.86%）;在筛查胎儿CNS畸形方面,产前超声敏感度、特异度、准确度分别为80.95%（68/84）、76.79%（86/112）、78.57%（154/196）,产前MRI分别为88.10%（74/84）、82.14%（92/112）、84.69%（166/196）,产前超声联合MRI分别为97.62%（82/84）、94.64%（106/112）、95.92%（188/196）,产前超声联合MRI明显优于产前超声、MRI,差异有统计学意义（P<0.05）。产前超声与MRI比较,差异无统计学意义（P>0.05）。本文证实了产前超声、MRI对胎儿CNS畸形具有良好的筛查价值,且二者联合的筛查价值更高。     

Functional micro/nanobubbles for ultrasound medicine and visualizable guidance

Chemically functionalized gas-filled bubbles with a versatile micro/nano-sized scale have witnessed a long history of developments and emerging applications in disease diagnosis and treatments. In combination with ultrasound and image-guidance,micro/nanobubbles have been endowed with the capabilities of biomedical imaging, drug delivery, gene transfection and diseaseoriented therapy. As an external stimulus, ultrasound(US)-mediated targeting treatments have been achieving unprecedented efficiency. Nowadays, US is playing a crucial role in visualizing biological/pathological changes in lives as a reliable imaging technique and a powerful therapeutic tool. This review retrospects the history of ultrasound, the chemistry of functionalized agents and summarizes recent advancements of functional micro/nanobubbles as US contrast agents in preclinical and transclinical research. Latest ultrasound-based treatment modalities in association with functional micro/nanobubbles have been highlighted as their great potentials for disease precision therapy. It is believed that these state-of-the-art micro/nanobubbles will become a booster for ultrasound medicine and visualizable guidance to serve future human healthcare in a more comprehensive and practical manner.     

Cover Picture: Nanomaterials for Fluorescence and Multimodal Bioimaging (Chem. Rec. 3/2023)

Bioconjugated nanomaterials replace molecular probes in bioanalysis and bioimaging in vitro and in vivo. Nanoparticles of silica, metals, semiconductors, polymers, and supramolecular systems, conjugated with contrast agents and drugs for image-guided (MRI, fluorescence, PET, Raman, SPECT, photodynamic, photothermal, and photoacoustic) therapy infiltrate into preclinical and clinical settings. Small bioactive molecules like peptides, proteins, or DNA conjugated to the surfaces of drugs or probes help us to interface them with cells and tissues. Nevertheless, the toxicity and pharmacokinetics of nanodrugs, nanoprobes, and their components become the clinical barriers, underscoring the significance of developing biocompatible next-generation drugs and contrast agents. This account provides state-of-the-art advancements in the preparation and biological applications of bioconjugated nanomaterials and their molecular, cell, and in vivo applications. It focuses on the preparation, bioimaging, and bioanalytical applications of monomodal and multimodal nanoprobes composed of quantum dots, quantum clusters, iron oxide nanoparticles, and a few rare earth metal ion complexes.     

血脑屏障通透性增效方法的研究进展

血脑屏障作为脑部的屏障系统,具有较强的保护作用,维持着中枢神经系统的内环境的稳定,同时也阻止药物进入脑部治疗中枢神经系统疾病。多年来,在提高血脑屏障通透性的研究方面有了很大进展,让药物靶向入脑,为治疗中枢神经系统疾病提供了很大的帮助。本文系统介绍血脑屏障的结构,其中主要介绍产生血脑屏障的解剖和功能结构,并对提高其通透性的增效方法和机制进行了概括,主要从物理、化学、生物学和纳米给药载体等方面阐述了提高血脑屏障透过方式,并简要介绍了一些具体药物的输送的应用。     

Recent advances in development of devices and probes for sensing and imaging in the brain

As the most important part of the central nervous system, the brain is extremely complex in structure and function. In vivo analysis of chemical signals is an essential way to investigate brain activity and function. Although functional magnetic resonance imaging(fMRI) or electrophysiology can be used to record brain activity, they are usually limited by low spatiotemporal fidelity or the difficulty of distinguishing the contributions of various neurochemicals. In addition, the development of in vivo biosensors with high selectivity and accuracy is essential to understand the roles that neurochemicals play in the brain. In this review, we focus on the development of instruments and devices for recording chemical signals in the live brain. Meanwhile,the strategies for development of electrochemical and fluorescent probes with high selectivity, high accuracy and good stability are also summarized. In particular, this review highlighted the contributions of our research group to this field. The development of techniques and probes enable us to understand the brain structure and function, and the mechanism of brain diseases, providing the solution for preventing and treating brain diseases.