Synthesis and Evaluation of GdIII‐Based Magnetic Resonance Contrast Agents for Molecular Imaging of Prostate‐Specific Membrane Antigen

Magnetic resonance (MR) imaging is advantageous because it concurrently provides anatomic, functional, and molecular information. MR molecular imaging can combine the high spatial resolution of this established clinical modality with molecular profiling in vivo. However, as a result of the intrinsically low sensitivity of MR imaging, high local concentrations of biological targets are required to generate discernable MR contrast. We hypothesize that the prostate‐specific membrane antigen (PSMA), an attractive target for imaging and therapy of prostate cancer, could serve as a suitable biomarker for MR‐based molecular imaging. We have synthesized three new high‐affinity, low‐molecular‐weight Gd^III‐based PSMA‐targeted contrast agents containing one to three Gd^III chelates per molecule. We evaluated the relaxometric properties of these agents in solution, in prostate cancer cells, and in an in vivo experimental model to demonstrate the feasibility of PSMA‐based MR molecular imaging.     

Dual‐Frequency Calcium‐Responsive MRI Agents

Responsive or smart magnetic resonance imaging (MRI) contrast agents are molecular sensors that alter the MRI signal upon changes in a particular parameter in their microenvironment. Consequently, they could be exploited for visualization of various biochemical events that take place at molecular and cellular levels. In this study, a set of dual‐frequency calcium‐responsive MRI agents are reported. These are paramagnetic, fluorine‐containing complexes that produce remarkably high MRI signal changes at the ¹H and ¹⁹F frequencies at varying Ca²⁺ concentrations. The nature of the processes triggered by Ca²⁺ was revealed, allowing a better understanding of these complex systems and their further improvement. The findings indicate that these double‐frequency tracers hold great promise for development of novel functional MRI methods.     

Mn2＋-NaY型分子筛作为口服胃肠道MRI造影剂的研究

用离子交换法制备了Mn^2＋交换的NaY分子筛MnNaY, 用红外光谱(IR)和X射线粉末衍射(XRD)等方法进行了表征. 研究了Mn^2＋含量为3.2%的样品在酸性水溶液中的稳定性和离子交换选择性. 弛豫时间测量和体内磁共振成像实验表明其弛豫效率变化范围为4.9～9.7 mmol•L•s^－1, 高于目前临床所用造影剂Gd-DTPA, 对胃部MRI信号具有良好的增强效果. 它是比较好的潜在口服胃肠道造影剂.     

一类肝靶向含钆大环磁共振对比剂的设计、制备与性能表征

肝靶向磁共振对比剂有助于肝细胞癌的早期诊断, 目前临床使用的线性对比剂存在导致病人肾源性系统性纤维化和钆离子沉积的风险. 本工作设计制备了一类含有乙氧芳基或甲氧苯基亲脂性基团、以DOTA-酰肼(DOTA: 1,4,7,10-tetraazacyclododecan-1,4,7,10-tetraacetic acid)为Gd³⁺离子螯合基团的大环类磁共振对比剂. 0.5 T磁场下测得其纵向弛豫率r₁值介于3.7~5.4 L•mmol^-1•s^-1, 优于临床使用对比剂Gd-DOTA, 弛豫率最高的为对比剂7h (Gd-DOTAH-EOPEI) (EOPEI: 1-(4-ethoxyphenyl)ethanimine), 略高于临床使用肝靶向对比剂Gd-EOB-DTPA (EOB: ethoxybenzyl; DTPA: diethylenetriaminepentaacetic acid), 比我们前期制得的肝靶向磁共振对比剂5d提高了约15%. 动物活体体内肝靶向磁共振成像研究显示, 所制备对比剂7b、7g和7h具有作为肝靶向磁共振对比剂的应用潜力. 结合弛豫率和活体体内成像数据, 筛选出了先导化合物7h.     

Cleaved Iron Oxide Nanoparticles as T2 Contrast Agents for Magnetic Resonance Imaging

Iron oxide nanoparticles as contrast agents are reported to effectively improve magnetic resonance imaging of tissues and cells. In this work, cleaved iron oxide nanoparticles (CIONPs) were generated from hydrophobic FeO nanoparticles (HIONPs) by coating their surfaces with PEG‐phospholipids, oxidizing them under water, and slowly removing the residual FeO phase in phthalate buffer. The synthesized CIONPs showed good r₂ values of up to 258 s^?1 mM ^?1. Thus, the CIONPs can be employed as vectors for drug delivery due to their unique structure with an empty inner space, which enables their use in a wide range of applications.     

磁共振成像造影剂的研究进展

磁共振成像技术已成为临床医学影像学检查的重要手段,30%以上的磁共振成像诊断需要使用造影剂,因此磁共振成像造影剂也成为一种重要的临床诊断药物.本文简单介绍磁共振成像造影剂的定义、原理和分类,并对当前的研究进展进行了的评述,认为开发具有靶向性、高弛豫效率、使用安全的造影剂是研究的主要方向.     

Cyclodextrin‐Based Bimodal Fluorescence/MRI Contrast Agents: An Efficient Approach to Cellular Imaging

A novel bimodal fluorescence/MRI probe based on a cyclodextrin scaffold has been synthesized and characterized. The final agent employs the fluorescein (F) functionality as a fluorescence marker and the Gd^III complex of a macrocyclic DOTA‐based ligand (GdL) having one aminobenzyl‐phosphinic acid pendant arm as an MRI probe, and has a statistical composition of (GdL)_6.9‐F_0.1‐β‐CD. Slow rotational dynamics (governed by a very rigid cyclodextrin scaffold) combined with fast water exchange (ensured by the chosen macrocyclic ligand) resulted in a high relaxivity of ～22 s^?1 mM ^?1 per Gd^III or ～150 s^?1 mM ^?1 per molecule of the final conjugate (20 MHz, 25 °C). In vitro labelling of pancreatic islets (PIs) and rat mesenchymal stem cells has been successfully performed. The agent is not cytotoxic and is easily internalized into cells. The labelled cells can be visualized by MRI, as proved by the detection of individual labelled PIs. A fluorescence study performed on mesenchymal stem cells showed that the agent stays in the intracellular space for a long time.     

Hyaluronic Acid‐Gadolinium Complex Nanospheres as Lymphatic System‐Specific Contrast Agent for Magnetic Resonance Imaging

A novel MRI contrast agent, hyaluronic acid gadolinium complex (HA‐Gd‐DTPA) nanospheres, is prepared by the synthesis of hyaluronic acid gadolinium complexes and their assembly. The physicochemical properties are characterized, and the lymphatic targeting in vitro and in vivo are also evaluated. The results show that the HA‐Gd‐DTPA nanospheres with suitable and stable physicochemical properties could be used for in vivo lymphatic targeting studies. Furthermore, the HA‐Gd‐DTPA nanospheres have obviously higher relaxation efficiency and MRI contrast between blood vessel and lymph vessel in rabbit than that of Magnevist. Thus, the novel MRI contrast agent can be taken up selectively by lymphatic system and used as a potential MRI contrast agents in lymphatic system.     

Self‐Aggregated Dinuclear Lanthanide(III) Complexes as Potential Bimodal Probes for Magnetic Resonance and Optical Imaging

Homodinuclear lanthanide complexes (Ln=La, Eu, Gd, Tb, Yb and Lu) derived from a bis‐macrocyclic ligand featuring two 2,2′,2′′‐(1,4,7,10‐tetraazacyclododecane‐1,4,7‐triyl)triacetic acid chelating sites linked by a 2,6‐bis(pyrazol‐1‐yl)pyridine spacer (H₂L³) were prepared and characterized. Luminescence lifetime measurements recorded on solutions of the Eu^III and Tb^III complexes indicate the presence of one inner‐sphere water molecule coordinated to each metal ion in these complexes. The overall luminescence quantum yields were determined (?=0.01 for [Eu₂(L³)] and 0.50 for [Tb₂(L³)] in 0.01 M TRIS/HCl, pH 7.4; TRIS=tris(hydroxymethyl)aminomethane), pointing to an effective sensitization of the metal ion by the bispyrazolylpyridyl unit of the ligand, especially with Tb. The nuclear magnetic relaxation dispersion (NMRD) profiles recorded for [Gd₂(L³)] are characteristic of slowly tumbling systems, showing a low‐field plateau and a broad maximum around 30 MHz. This suggests the occurrence of aggregation of the complexes giving rise to slowly rotating species. A similar behavior is observed for the analogous Gd^III complex containing a 4,4′‐dimethyl‐2,2′‐bipyridyl spacer ([Gd₂(L¹)]). The relaxivity of [Gd₂(L³)] recorded at 0.5 T and 298 K (pH 6.9) amounts to 13.7 mM ^?1 s^?1. The formation of aggregates has been confirmed by dynamic light scattering (DLS) experiments, which provided mean particle sizes of 114 and 38 nm for [Gd₂(L¹)] and [Gd₂(L³)], respectively. TEM images of [Gd₂(L³)] indicate the formation of nearly spherical nanosized aggregates with a mean diameter of about 41 nm, together with some nonspherical particles with larger size.     

磁共振成像造影剂的一些进展

本文综述了近年来磁共振成像造影剂的一些研究进展,对70余种钆配合物作了分类讨论。     

Imaging Glycosylation In Vivo by Metabolic Labeling and Magnetic Resonance Imaging

Glycosylation is a ubiquitous post‐translational modification, present in over 50 % of the proteins in the human genome, 1 with important roles in cell–cell communication and migration. Interest in glycome profiling has increased with the realization that glycans can be used as biomarkers of many diseases, 2 including cancer. 3 We report here the first tomographic imaging of glycosylated tissues in live mice by using metabolic labeling and a gadolinium‐based bioorthogonal MRI probe. Significant N‐azidoacetylgalactosamine dependent T₁ contrast was observed in vivo two hours after probe administration. Tumor, kidney, and liver showed significant contrast, and several other tissues, including the pancreas, spleen, heart, and intestines, showed a very high contrast (>10‐fold). This approach has the potential to enable the rapid and non‐invasive magnetic resonance imaging of glycosylated tissues in vivo in preclinical models of disease.     

Calix[4]arenes as Molecular Platforms for Magnetic Resonance Imaging (MRI) Contrast Agents

The novel amphipilic conjugate of a calix[4]arene with four Gd–1,4,7,10‐ tetra(carboxymethyl)‐1,4,7,10‐tetraazacyclododecane (DOTA) chelates has potential as a magnetic resonance imaging contrast agent, both in its monomeric and in its micellar form. The system, illustrated here with its nuclear magnetic relaxation profile, shows good relaxivities, thanks to its high rigidity.

     

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.     

Magneto‐Plasmonic Janus Vesicles for Magnetic Field‐Enhanced Photoacoustic and Magnetic Resonance Imaging of Tumors

Magneto‐plasmonic Janus vesicles (JVs) integrated with gold nanoparticles (AuNPs) and magnetic NPs (MNPs) were prepared asymmetrically in the membrane for in vivo cancer imaging. The hybrid JVs were produced by coassembling a mixture of hydrophobic MNPs, free amphiphilic block copolymers (BCPs), and AuNPs tethered with amphiphilic BCPs. Depending on the size and content of NPs, the JVs acquired spherical or hemispherical shapes. Among them, hemispherical JVs containing 50 nm AuNPs and 15 nm MNPs showed a strong absorption in the near‐infrared (NIR) window and enhanced the transverse relaxation (T₂) contrast effect, as a result of the ordering and dense packing of AuNPs and MNPs in the membrane. The magneto‐plasmonic JVs were used as drug delivery vehicles, from which the release of a payload can be triggered by NIR light and the release rate can be modulated by a magnetic field. Moreover, the JVs were applied as imaging agents for in vivo bimodal photoacoustic (PA) and magnetic resonance (MR) imaging of tumors by intravenous injection. With an external magnetic field, the accumulation of the JVs in tumors was significantly increased, leading to a signal enhancement of approximately 2–3 times in the PA and MR imaging, compared with control groups without a magnetic field.     

水溶性金属卟啉肿瘤靶向磁共振成像造影剂的研究

利用显微荧光－阿达玛变换三维图像分析研究了Ｃｕ－ＴＳＰＰ，Ｍｎ－ＴＳＰＰ，Ｃｕ－ＴＭＡＰ，Ｍｎ－ＴＭＡＰ４种水溶性金属卟啉人细胞间质进入肿瘤细胞内的富集过程，对金属卟啉的自旋－晶格驰豫性能（Ｒ１）的天空结果表明，Ｍｎ（Ⅱ）卟啉配合物的Ｒ１、值结Ｇｄ－ＤＴＰＡ提高１．５－２倍。     

Yttrium‐86 Is a Positron Emitting Surrogate of Gadolinium for Noninvasive Quantification of Whole‐Body Distribution of Gadolinium‐Based Contrast Agents

Gadolinium‐based contrast agents (GBCAs) are used to provide diagnostic information in clinical magnetic resonance (MR) examinations. Gadolinium (Gd) has been detected in the brain, bone and skin of patients, months and years following GBCA administration, raising concerns about long term toxicity. Despite increased scrutiny, the concentration, chemical form and fate of the retained gadolinium species remain unknown. Importantly, the whole body biodistribution and organ clearance of GBCAs is poorly understood in humans. Gadolinium lacks suitable isotopes for nuclear imaging. We demonstrate that the yttrium‐86 isotope can be used as a gadolinium surrogate. We show that Gd and their analogous Y complexes have similar properties both in solution and in vivo, and that yttrium‐86 PET can be used to track the biodistribution of GBCAs over a two‐day period.