“Clickable” Hydrosoluble PEGylated Cryptophane as a Universal Platform for 129Xe Magnetic Resonance Imaging Biosensors

We describe the synthesis of a highly water‐soluble cryptophane 1 that can be seen as a universal platform for the construction of ¹²⁹Xe magnetic resonance imaging (MRI)‐based biosensors. Compound 1 is easily functionalized by Huisgen cycloaddition and exhibits excellent xenon‐encapsulation properties. In addition, 1 is nontoxic at the concentrations typically used for hyperpolarized ¹²⁹Xe MRI.     

A Xenon‐129 Biosensor for Monitoring MHC–Peptide Interactions

Caged in : The formation of a complex between a peptide ligand and a major histocompatibility complex (MHC) class II protein is detected by a ¹²⁹Xe biosensor. Cryptophane molecules that trap Xe atoms are modified with a hemagglutinin (HA) peptide, which binds to the MHC protein. The interaction can be monitored by an NMR chemical shift change of cage–HA bound ¹²⁹Xe.

     

Biomembrane Interactions of Functionalized Cryptophane‐A: Combined Fluorescence and 129Xe NMR Studies of a Bimodal Contrast Agent

Fluorescent derivatives of the ¹²⁹Xe NMR contrast agent cryptophane‐A were obtained by functionalization with near infrared fluorescent dyes DY680 and DY682. The resulting conjugates were spectrally characterized, and their interaction with giant and large unilamellar vesicles of varying phospholipid composition was analyzed by fluorescence and NMR spectroscopy. In the latter, a chemical exchange saturation transfer with hyperpolarized ¹²⁹Xe (Hyper‐CEST) was used to obtain sufficient sensitivity. To determine the partitioning coefficients, we developed a method based on fluorescence resonance energy transfer from Nile Red to the membrane‐bound conjugates. This indicated that not only the hydrophobicity of the conjugates, but also the phospholipid composition, largely determines the membrane incorporation. Thereby, partitioning into the liquid‐crystalline phase of 1,2‐dipalmitoyl‐sn‐glycero‐3‐phosphocholine was most efficient. Fluorescence depth quenching and flip‐flop assays suggest a perpendicular orientation of the conjugates to the membrane surface with negligible transversal diffusion, and that the fluorescent dyes reside in the interfacial area. The results serve as a basis to differentiate biomembranes by analyzing the Hyper‐CEST signatures that are related to membrane fluidity, and pave the way for dissecting different contributions to the Hyper‐CEST signal.     

Magnetic Resonance of Paramagnetic Complexes

The line width of the ESR and NMR signals of paramagnetic transition metal complexes is determined mainly by the electron spin-lattice relaxation time τ_e. Values of τ_e greater than 10^?9 lead to ESR spectra that are readily resolved, while values smaller than 10^?11 give NMR spectra having small line widths. Since fast relaxation processes are effective in nearly all transition metal complexes with several unpaired electrons and in all complexes having an orbitally degenerate ground state, the NMR method has a wider scope. The sign and magnitude of the electron-nucleus coupling can be determined with great sensitivity from the NMR spectra, whereas only the magnitude of this interaction can be determined from the ESR spectra. Free spin densities can be found very accurately from the NMR shifts, and the method can therefore be advantageously applied to kinetic measurements, e.g. on short-lived contact complexes.     

Methods and Applications of Nuclear Magnetic Double Resonance

In double resonance spectra, transitions between energy levels of a nuclear spin system are measured in the presence of two (or more) oscillating magnetic fields. Experiments of this nature form the basis of what is nowadays one of the most important techniques of NMR spectroscopy. Depending on the method selected, they can be used to unravel complex spectra, to measure hidden or weak resonances, or to determine the relative signs of coupling constants, as well as in stereochemical or kinetic studies. This wide and steadily growing range of applications of double resonance is described with the aid of specifilc examples.     

新型生物相容性大分子磁共振成像造影剂的性质研究

将天冬氨酸与亮氨酸反应,合成了天冬氨酸-亮氨酸共聚物(PL),通过乙二胺将钆-1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸(Gd-DOTA)连接到PL上,制备了大分子磁共振成像造影剂PL-A2-DOTA-Gd,通过核磁碳谱、凝胶色谱等方法对其结构进行了表征,利用细胞毒性实验、溶血性实验、体外弛豫效率测定以及体内动物磁共振成像等方法对其性能进行了评估。研究表明,PL-A2-DOTA-Gd的细胞毒性远低于临床应用的造影剂Gd-DOTA,且其弛豫效率(15.3 L/(mmol·s))是Gd-DOTA(5.8 L/(mmol·s))的2.6倍。大分子磁共振成像造影剂PL-A2-DOTA-Gd具有良好的血液相容性,对昆明小鼠的肝脏信号的增强效果约为Gd-DOTA的3.1倍,且能在较长时间内保持良好稳定的增强效果。     

In Vivo Detection of Copper Ions by Magnetic Resonance Imaging Using a Prion-Based Contrast Agent

Abnormal distributions of transition metals inside the body are potential diagnostic markers for several diseases, including Alzheimer's disease, Parkinson's disease, Wilson??s disease, and cancer. In this article, we demonstrate that P57/Gd, a novel prion-based contrast agent, can selectively image tissues with excessive copper accumulation using magnetic resonance imaging (MRI). P57/Gd selectivity binds copper(II) over other physiologically relevant cations such as zinc, iron, manganese, and calcium. To simulate a metabolic copper disorder, we treated mice with an intraperitoneal injection of a CuSO₄ solution to induce a renal copper overload. The MRI signal intensities from the renal cortex and medulla of copper spiked animals that were administered P57/Gd were found to correlate with the ex vivo copper concentrations determined by inductively coupled plasma mass spectrometry.     

Optimized use of reversible binding for fast and selective NMR localization of caged xenon

The NMR signal of hyperpolarized (129) Xe trapped in cryptophane cages in different solvents experiences different chemical shifts. An encoding method is presented that involves the optimal use of reversible Xe binding and efficiently uses hyperpolarization. This method is utilized in nanomolar imaging, subsecond imaging, and time-resolved studies while maintaining high spectral selectivity.     

The Detection and Reactivity of Silanols and Silanes Using Hyperpolarized 29Si Nuclear Magnetic Resonance

Silanols and silanes are key precursors and intermediates for the synthesis of silicon‐based materials. While their characterization and quantification by ²⁹Si NMR spectroscopy has received significant attention, it is a technique that is limited by the low natural abundance of ²⁹Si and its low sensitivity. Here, we describe a method using p‐H₂ to hyperpolarize ²⁹Si. The observed signal enhancements, approaching 3000‐fold at 11.7 T, would take many days of measurement for comparable results under Boltzmann conditions. The resulting signals were exploited to monitor the rapid reaction of tris(tert‐butoxy)silanol with triflic anhydride in a T₁‐corrected process that allows for rapid quantification. These results demonstrate a novel route to quantify dynamic processes and intermediates in the synthesis of silicon materials.     

Gadolinium(III)-Based Dual 1H/19F Magnetic Resonance Imaging Probes

We present two novel octadentate cyclen-based ligands bearing one (L¹) or two (L²) phenylacetamide pendants with two CF₃ groups either at positions 3 and 5 (L¹) or 4 (L²). The corresponding Gd³⁺ complexes possess one coordinated water molecule, as confirmed by luminescence lifetime measurements on the Eu^III and Tb^III analogues. A detailed ¹H and ¹⁷O relaxometric characterization has revealed the parameters that govern the relaxivities of these complexes. The water-exchange rate of the mono-amide derivative GdL¹ (k_ex²⁹⁸=1.52×10⁶ s⁻¹) is faster than that determined for the bis-amide complex GdL² (k_ex²⁹⁸=0.73×10⁶ s⁻¹). ¹H and ¹⁹F NMR studies have indicated that the complexes are present in solution almost exclusively as the square-antiprismatic (SAP) isomers. ¹⁹F NMR relaxation studies indicated Gd ⋅⋅⋅ F distances of 7.4±0.1 and 9.1±0.1 Å for GdL¹ and GdL², respectively. Phantom MRI studies revealed the favorable properties of GdL² as a dual ¹H/¹⁹F magnetic resonance imaging (MRI) probe, whereas the shorter Gd ⋅⋅⋅ F distance of GdL¹ reduces the signal-to-noise ratio due to the very short transverse relaxation time of the ¹⁹F NMR signal.     

A Strategy to Design Hyperpolarized 13C Magnetic Resonance Probes Using [1‐13C]α‐Amino Acid as a Scaffold Structure

Hyperpolarization is an emerging method that dramatically enhances NMR signal intensity. As a result of their increased sensitivity, hyperpolarized (HP) NMR molecular probes can be used to perform time‐resolved spectroscopy and imaging in vitro and in vivo. It is, however, challenging to design such probes de novo. Herein, the [1‐¹³C]α‐amino acid is reported as a scaffold structure to design HP ¹³C NMR molecular probes. The [1‐¹³C]α‐amino acid can be converted to various HP ¹³C chemical probes that show sufficient chemical shift change by altering the chemical state of the α nitrogen upon interaction with the target. Several previously reported HP probes could be explained by this design principle. To demonstrate the versatility of this approach, two α‐amino‐acid‐based HP ¹³C chemical probes, sensitive to pH and Ca²⁺ ion, were developed and used to detect targets.     

A Hyperpolarizable 1H Magnetic Resonance Probe for Signal Detection 15 Minutes after Spin Polarization Storage

Nuclear magnetic resonance (NMR) and magnetic resonance imaging (MRI) are two extremely important techniques with applications ranging from molecular structure determination to human imaging. However, in many cases the applicability of NMR and MRI are limited by inherently poor sensitivity and insufficient nuclear spin lifetime. Here we demonstrate a cost‐efficient and fast technique that tackles both issues simultaneously. We use the signal amplification by reversible exchange (SABRE) technique to hyperpolarize the target ¹H nuclei and store this polarization in long‐lived singlet (LLS) form after suitable radiofrequency (rf) pulses. Compared to the normal scenario, we achieve three orders of signal enhancement and one order of lifetime extension, leading to ¹H NMR signal detection 15 minutes after the creation of the detected states. The creation of such hyperpolarized long‐lived polarization reflects an important step forward in the pipeline to see such agents used as clinical probes of disease.     

Synthesis and Properties of a Biodegradable Dendritic Magnetic Resonance Imaging Contrast Agent

Novel biodegradable dendritic contrast agents (DCAs) based on polyester dendrimers were synthesized and characterized.The DCAs were stable at acidic pH,but hydrolyzed rapidly at physiological pH,which rendered the DCA's long-term Gd3+ retention as low as that of small molecule CAs.Their longitudinal relaxivities of 10.2 to 17.5 L·mmol-1·s-1 were about 2.4 to 4.1 times higher than that of DTPA-Gd,indicating their superior contrast-enhancing capability to the clinically used contrast agent.The in vivo MRI study suggested that the DCA at lower generation (G2-DTPA-Gd) could effectively enhance the MRI of tumor,while the one at higher generation (G5-DTPA-Gd) showed more potential in liver imaging.     

Review and Prospect: Deep Learning in Nuclear Magnetic Resonance Spectroscopy

Since the concept of deep learning (DL) was formally proposed in 2006, it has had a major impact on academic research and industry. Nowadays, DL provides an unprecedented way to analyze and process data with demonstrated great results in computer vision, medical imaging, natural language processing, and so forth. Herein, applications of DL in NMR spectroscopy are summarized, and a perspective for DL as an entirely new approach that is likely to transform NMR spectroscopy into a much more efficient and powerful technique in chemistry and life sciences is outlined.     

动脉粥样硬化造影剂PGMA-EDA-g-PEG-g-DS@IO的合成及性能

利用乙二胺(EDA)对聚甲基丙烯酸缩水甘油酯(PGMA)进行开环反应, 制备了侧链多氨基聚合物PGMA-EDA; 再利用聚乙二醇(PEG-COOH)和硫酸葡聚糖钠盐(DS)分别对PGMA-EDA上氨基进行酰胺化反应和还原胺化反应, 制备含动脉粥样硬化斑块靶向分子DS的双亲性接枝共聚物PGMA-EDA-g-PEG-g-DS. 通过核磁共振(¹H NMR)谱和红外光谱(FTIR)表征了聚合物的结构. 利用凝胶渗透色谱(GPC)表征了聚合物的数均分子量M_n=16255, 多分散性指数PDI=1.54. 采用配体交换法, 利用该聚合物对油胺配体超顺磁性氧化铁纳米粒子进行修饰, 制备了水溶性氧化铁纳米粒子PGMA-EDA-g-PEG-g-DS@IO. 通过透射电镜(TEM)和动态光散射(DLS)表征了纳米粒子的形貌和粒度, 采用热重分析(TGA)和振动样品磁强(VSM)仪表征了纳米粒子的包覆率和磁强度. 采用细胞计数试剂盒(CCK)测定了纳米粒子的细胞毒性, 结果表明, 水溶性纳米粒子的生物相容性较好, 可作为动脉粥样硬化斑块的特异性磁共振检测用造影剂.