Effect of x-ray contrast substances on the complement system of rats

The purpose of the work was to demonstrate the effect of radiographic contrast media (RCM) 50% bilignost, 76% triombrast, 80% iodamide-380 on the complement system in rats. It has been found that RCM cause alternative complement activation during incubation with the whole blood or serum in vivo and in vitro. The RCM effect value depends on the drug dose and increase in the order: triombrast iodamide bilignost. Different sensitivity of animals to the effect of RCM on the complement system has been shown.     

Dendrimer-based macromolecular MRI contrast agents: characteristics and application

Numerous macromolecular MRI contrast agents prepared employing relatively simple chemistry may be readily available that can provide sufficient enhancement for multiple applications. These agents operate using a approximately 100-fold lower concentration of gadolinium ions in comparison to the necessary concentration of iodine employed in CT imaging. Herein, we describe some of the general potential directions of macromolecular MRI contrast agents using our recently reported families of dendrimer-based agents as examples. Changes in molecular size altered the route of excretion. Smaller-sized contrast agents less than 60 kDa molecular weight were excreted through the kidney resulting in these agents being potentially suitable as functional renal contrast agents. Hydrophilic and larger-sized contrast agents were found better suited for use as blood pool contrast agents. Hydrophobic variants formed with polypropylenimine diaminobutane dendrimer cores created liver contrast agents. Larger hydrophilic agents are useful for lymphatic imaging. Finally, contrast agents conjugated with either monoclonal antibodies or with avidin are able to function as tumor-specific contrast agents, which also might be employed as therapeutic drugs for either gadolinium neutron capture therapy or in conjunction with radioimmunotherapy.     

Water-soluble contrast media with increased viscosity for the diagnosis of diseases of the paranasal sinuses, bronchi and esophagus]

Water-soluble contrast agents with one of the polymers, cellulose derivatives or polyvinyl alcohol, were used in contrast examinations of paranasal sinuses, bronchi, and esophagus. Experiments have demonstrated the advantages of contrast agents basing on polymers as against the traditional oil-containing agents. Method for double-contrast examination of maxillary and frontal sinuses has been developed. Lowered concentrations of water-soluble contrast agents (i. e. diluted with distilled water) are recommended to be used, this permitting to save the reagents. A table of recommended dilutions of contrast media is presented. A total of 245 patients were examined, making use of contrast media of high viscosity.     

Tailoring the size distribution of ultrasound contrast agents: possible method for improving sensitivity in molecular imaging

Encapsulated microbubble contrast agents incorporating an adhesion ligand in the microbubble shell are used for molecular imaging with ultrasound. Currently available microbubble agents are produced with techniques that result in a large size variance. Detection of these contrast agents depends on properties related to the microbubble diameter such as resonant frequency, and current ultrasound imaging systems have bandwidth limits that reduce their sensitivity to a polydisperse contrast agent population. For ultrasonic molecular imaging, in which only a limited number of targeted contrast agents may be retained at the site of pathology, it is important to optimize the sensitivity of the imaging system to the entire population of contrast agent. This article presents contrast agents with a narrow size distribution that are targeted for molecular imaging applications. The production of a functionalized, lipid-encapsulated, microbubble contrast agent with a monodisperse population is demonstrated, and we evaluate parameters that influence the size distribution and demonstrate initial acoustic testing.     

CT检查中造影剂不良反应的预防、处理及对影像学检查的影响分析

目的：在CT等医学影像检查过程中,常需要应用造影剂。在造影剂的使用常常发生不良反应,掌握不良反应的发生率,减少或减轻患者的不良反应,能够使CT增强扫描顺利进行,提高检查安全性。方法：搜集我院2011年10月至2012年9月间的1500例CT造影增强检查患者,包括冠状动脉CT血管成像（冠脉CTA）、头部CT血管成像（头CTA）、肝脏增强、泌尿系三维成像（CTU）以及双下肢血管成像（双下肢CTA）,进行造影剂的不良反应类型、造影剂药物剂量、注射速度等统计分析,总结造成不良反应发生的因素及处理方法。结果：不良反应的类型包括发热、呕吐、荨麻疹、面色潮红、局部疼痛、流泪、血压下降、喉头水肿、休克等。使用非离子型造影剂出现不良反应者85例,占5．67％。其中轻度反应65例,占4．33％;中度反应16例,占1．06％;重度4例,占0．27％。结论：在CT增强扫描过程中,造影剂的用量及注射速度与不良反应的发生有相关性。cT检查过程总应该认真执行操作流程,密切观察病人情况,积极防治,正确处理,将造影剂不良反应降低到最低程度,使患者更加安全。     

Switchable MRI contrast agents based on morphological changes of pH-responsive polymers

Magnetic resonance imaging (MRI) contrast agents are effective tools in both medical diagnosis and life science research. Various smart contrast agents have been developed for the visualization of biological phenomena. These contrast agents have molecular switches that increase or reduce MRI signal intensity in response to the target biological reaction. Therefore, novel approaches to the design of molecular switches for versatile in vivo studies using MRI are eagerly anticipated. Here, we report one such approach for the development of molecular switches based on morphological changes of pH-responsive polymers. We designed and synthesized three types of contrast agents based on a linear homopolymer or spherical copolymers with two different cross-linking degrees. The relaxivity measurements showed that these agents have molecular switches that respond to pH changes, and fluorescence studies indicated that these switches are based on the alteration of the molecular tumbling caused by pH-responsive morphological changes. As a result, the spherical polymers possess promising characteristics for the development of switchable MRI contrast agents.     

CT检查中造影剂不良反应的预防、处理及对影像学检查 的影响分析

目的：在CT 等医学影像检查过程中,常需要应用造影剂。在造影剂的使用常常发生不良反应,掌握不良反应的发生率,减少 或减轻患者的不良反应,能够使CT 增强扫描顺利进行,提高检查安全性。方法：搜集我院2011 年10 月至2012 年9 月间的1500 例CT 造影增强检查患者,包括冠状动脉CT 血管成像（冠脉CTA）、头部CT 血管成像（头CTA）、肝脏增强、泌尿系三维成像 （CTU）以及双下肢血管成像（双下肢CTA）,进行造影剂的不良反应类型、造影剂药物剂量、注射速度等统计分析,总结造成不良 反应发生的因素及处理方法。结果：不良反应的类型包括发热、呕吐、荨麻疹、面色潮红、局部疼痛、流泪、血压下降、喉头水肿、休 克等。使用非离子型造影剂出现不良反应者85 例,占5.67 %。其中轻度反应65 例,占4. 33%;中度反应16 例,占1.06%;重度4 例,占0. 27 %。结论：在CT 增强扫描过程中,造影剂的用量及注射速度与不良反应的发生有相关性。ＣＴ 检查过程总应该认真 执行操作流程,密切观察病人情况,积极防治,正确处理,将造影剂不良反应降低到最低程度,使患者更加安全。     

Oligonucleotide-coated metallic nanoparticles as a flexible platform for molecular imaging agents

Targeted metallic nanoparticles have shown promise as contrast agents for molecular imaging. To obtain molecular specificity, the nanoparticle surface must be appropriately functionalized with probe molecules that will bind to biomarkers of interest. The aim of this study was to develop and characterize a flexible approach to generate molecular imaging agents based on gold nanoparticles conjugated to a diverse range of probe molecules. We present two complementary oligonucleotide-based approaches to develop gold nanoparticle contrast agents which can be functionalized with a variety of biomolecules ranging from small molecules, to peptides, to antibodies. The size, biocompatibility, and protein concentration per nanoparticle are characterized for the two oligonucleotide-based approaches; the results are compared to contrast agents prepared using adsorption of proteins on gold nanoparticles by electrostatic interaction. Contrast agents prepared from oligonucleotide-functionalized nanoparticles are significantly smaller in size and more stable than contrast agents prepared by adsorption of proteins on gold nanoparticles. We demonstrate the flexibility of the oligonucleotide-based approach by preparing contrast agents conjugated to folate, EGF peptide, and anti-EGFR antibodies. Reflectance images of cancer cell lines labeled with functionalized contrast agents show significantly increased image contrast which is specific for the target biomarker. To demonstrate the modularity of this new bioconjugation approach, we use it to conjugate both fluorophore and anti-EGFR antibodies to metal nanoparticles, yielding a contrast agent which can be probed with multiple imaging modalities. This novel bioconjugation approach can be used to prepare contrast agents targeted with biomolecules that span a diverse range of sizes; at the same time, the bioconjugation method can be adapted to develop multimodal contrast agents for molecular imaging without changing the coating design or material.     

PEGylation of protein-based MRI contrast agents improves relaxivities and biocompatibilities

Magnetic resonance imaging (MRI) has emerged as a leading diagnostic technique in clinical and preclinical settings. However, the application of MRI to assess specific disease markers for diagnosis and monitoring drug effect has been severely hampered by the lack of desired contrast agents with high relaxivities, and optimized in vivo retention time. We have reported the development of protein-based MRI contrast agents (ProCA1) by rational design of Gd^3 + binding sites into a stable protein resulting in significantly increased longitudinal (r₁) and transverse (r₂) relaxivities compared to Gd-DTPA. Here, we report a further improvement of protein contrast agents ProCA1 for in vivo imaging by protein modification with various sizes of polyethylene glycol (PEG) chain. PEGylation results in significant increases of both r₁ and r₂ relaxivities (up to 200%), and these high relaxivities persist even at field strengths up to 9.4 T. In addition, our experimental results demonstrate that modified contrast agents have significant improvement of in vivo MR imaging and biocompatibilities including dose efficiency, protein solubility, blood retention time and decreased immunogenicity. Such improvement can be important to the animal imaging and pre-clinical research at high or ultra-high field where there is an urgent need for molecular imaging probes and optimized contrast agent.     

Contrast agents for MRI: 30+ years and where are we going?

Thirty years ago, Schering filed the first patent application for a contrast agent for magnetic resonance imaging (MRI) covering the forefather of the gadolinium contrast agents and still the most widely used gadolinium probe: gadolinium(III) diethylenetriaminepentaacetate (Magnevist). To date, 11 contrast agents have been approved by the US Food and Drug Administration for intravenous use. Coordination chemists have done a great deal to move the field forward. Our understanding of lanthanide chemistry now makes possible the design of complexes with long rotational correlation times, fast or slow water-exchange rates, high thermodynamic stabilities, and kinetic inertness, leading to sensitive and nontoxic contrast agents. Chemists did not stop there. The last few decades has seen the development of novel classes of probes that yield contrast through different mechanisms, such as paramagnetic chemical exchange saturation transfer agents. Thirty years since the first patent, chemists are still leading the way. The development of high-sensitivity contrast agents for high magnetic fields, safe probes for patients with kidney disorders, and multimodal, targeted, and responsive agents demonstrates that the field of contrast agents for MRI still has much to offer.     

MRI contrast agents for functional molecular imaging of brain activity

Functional imaging with MRI contrast agents is an emerging experimental approach that can combine the specificity of cellular neural recording techniques with noninvasive whole-brain coverage. A variety of contrast agents sensitive to aspects of brain activity have recently been introduced. These include new probes for calcium and other metal ions that offer high sensitivity and membrane permeability, as well as imaging agents for high-resolution pH and metabolic mapping in living animals. Genetically encoded MRI contrast agents have also been described. Several of the new probes have been validated in the brain; in vivo use of other agents remains a challenge. This review outlines advantages and disadvantages of specific molecular imaging approaches and discusses current or potential applications in neurobiology.     

Polydisulfide Gd(III) chelates as biodegradable macromolecular magnetic resonance imaging contrast agents

Macromolecular gadolinium (Gd)(III) complexes have a prolonged blood circulation time and can preferentially accumulate in solid tumors, depending on the tumor blood vessel hyperpermeability, resulting in superior contrast enhancement in magnetic resonance (MR) cardiovascular imaging and cancer imaging as shown in animal models. Unfortunately, safety concerns related to these agents' slow elimination from the body impede their clinical development. Polydisulfide Gd(III) complexes have been designed and developed as biodegradable macromolecular magnetic resonance imaging (MRI) contrast agents to facilitate the clearance of Gd(III) complexes from the body after MRI examinations. These novel agents can act as macromolecular contrast agents for in vivo imaging and excrete rapidly as low-molecular-weight agents. The rationale and recent development of the novel biodegradable contrast agents are reviewed here. Polydisulfide Gd(III) complexes have relatively long blood circulation time and gradually degrade into small Gd(III) complexes, which are rapidly excreted via renal filtration. These agents result in effective and prolonged in vivo contrast enhancement in the blood pool and tumor tissue in animal models, yet demonstrate minimal Gd(III) tissue retention as the clinically used low-molecular-weight agents. Structural modification of the agents can readily alter the contrast-enhancement kinetics. Polydisulfide Gd(III) complexes are promising for further clinical development as safe, effective, biodegradable macromolecular MRI contrast agents for cardiovascular and cancer imaging, and for evaluation of therapeutic response.     

超声空化效应和超声微泡在生物医学中的应用

近年来,随着超声技术在医疗领域的广泛应用及超声造影剂研制的进展,空化效应和超声造影剂协同运用作为一种高效、安全、操作简单,且具有一定靶向性的无创治疗手段,在基因治疗、药物输送、溶栓和治栓,以及炎症与肿瘤的靶向诊断与治疗方面显示了巨大的运用潜力。简要综述了超声空化效应和超声微泡的治疗机制及应用。     

Water-soluble polysaccharides as carriers of paramagnetic contrast agents for magnetic resonance imaging: synthesis and relaxation properties.

Water-soluble, carbohydrate-based, paramagnetic metal chelate derivatives have been investigated as potential organ-selective contrast media for magnetic resonance imaging (m.r.i.). The in vitro proton spin-lattice relaxation properties of compounds with different paramagnetic metals, chelating agents, and carbohydrate matrixes have been studied. Typically, these complexes were 60-260% more efficient proton-relaxation agents than the corresponding low-molecular-weight metal chelates at 10 MHz, but less efficient than the corresponding protein derivatives. As expected, carbohydrates that contained manganese or gadolinium were more effective relaxation agents than iron, copper, erbium, or nickel derivatives.     

Synthesis and characterization of ethosomal contrast agents containing iodine for computed tomography (CT) imaging applications

As a first step in the development of novel liver-specific contrast agents using ethosomes for computed tomography (CT) imaging applications, we entrapped iodine within ethosomes, which are phospholipid vesicular carriers containing relatively high alcohol concentrations, synthesized using several types of alcohol, such as methanol, ethanol, and propanol. The iodine containing ethosomes that were prepared using methanol showed the smallest vesicle size (392?nm) and the highest CT density (1107 HU). The incorporation of cholesterol into the ethosomal contrast agents improved the stability of the ethosomes but made the vesicle size large. The ethosomal contrast agents were taken up well by macrophage cells and showed no cellular toxicity. The results demonstrated that ethosomes containing iodine, as prepared in this study, have potential as contrast agents for applications in CT imaging.     

Use of lanthanide-grafted inorganic nanoparticles as effective contrast agents for cellular uptake imaging

The improvement of commonly used Gd3+ -based MRI agents requires the design of new systems with optimized in vivo efficacy, pharmacokinetic properties, and specificity. To design these contrast agents, two parameters are usually considered: increasing the number of coordinated water molecules or increasing the rotational correlation time by increasing molecular weight and size. This has been achieved by noncovalent or covalent binding of low-molecular weight Gd3+ chelates to macromolecules or polymers. The grafting of these high-spin paramagnetic gadolinium chelates on metal oxide nanoparticles (SiO2, Al2O3) is proposed. This new synthetic strategy presents at least two main advantages: (1) a high T1-relaxivity for MRI with a 275% increase of the MRI signal and (2) the ability of nanoparticles to be internalized in cells. Results indicate that these new contrast agents lead to a huge reconcentration of Gd3+ paramagnetic species inside microglial cells. This reconcentration phenomenon gives rise to high signal-to-noise ratios on MR images of cells after particle internalization, from 1.4 to 3.75, using Al2O3 or SiO2 particles, respectively. The properties of these new particles will be further used to get new insight into gene therapy against glioma, using microglial cells as vehicles to simultaneously transport a suicide gene and contrast agents. Since microglia are chemoattracted to brain tumors, the presence of these new contrast agents inside the cells will lead to a better MRI determination of the in vivo location, shape, and borders of the tumors. These Gd3+-loaded microglia can therefore provide effective localization of tumors by MRI before applying any therapeutic treatment. The rate of carcinoma remission following a suicide gene strategy is also possible.     

The involvement of osmolarity in the safety of contrast media

Background

New non-ionic contrast agents, classified into low osmolar agents and iso-osmolar agents, present different biochemical characteristics that may influence the allergic reactions they cause. The aim of our study was to evaluate how osmolarity may affect safety in the use of contrast agents.

Case presentation

Six patients with a positive history for reaction to contrast agent were included in this study. Only one patient prick and intradermal skin test was positive. However, in 5 cases, patients presented an immediate reaction after administration of contrast agent that was not IgE mediated.

Conclusions

In this study, we focused on iodixanol, an iso-osmolar contrast agent, finding good safety of this product in patients with previous hypersensitivity reactions to contrast agent.

     

Macromolecular MRI contrast agents with small dendrimers: pharmacokinetic differences between sizes and cores

Large macromolecular MRI contrast agents with albumin or dendrimer cores are useful for imaging blood vessels. However, their prolonged retention is a major limitation for clinical use. Although smaller dendrimer-based MRI contrast agents are more quickly excreted by the kidneys, they are also able to visualize vascular structures better than Gd-DTPA due to less extravasation. Additionally, unlike Gd-DTPA, they transiently accumulate in renal tubules and thus also can be used to visualize renal structural and functional damage. However, these dendrimer agents are retained in the body for a prolonged time. The purpose of this study was to obtain information from which a macromolecular dendrimer-based MRI contrast agents feasible for use in further clinical studies could be chosen. Six small dendrimer-based MRI contrast agents were synthesized, and their pharmacokinetics, whole-body retention, and dynamic MRI were evaluated in mice to determine an optimal agent in comparison to Gd-[DTPA]-dimeglumine. Diaminobutane (DAB) dendrimer-based agents cleared more rapidly from the body than polyamidoamine (PAMAM) dendrimer-based agents with the same numbers of branches. Smaller dendrimer conjugates were more rapidly excreted from the body than the larger dendrimer conjugates. Since PAMAM-G2, DAB-G3, and DAB-G2 dendrimer-based contrast agents showed relatively rapid excretion, these three conjugates might be acceptable for use in further clinical applications.     

Inorganic nanoparticle-based contrast agents for molecular imaging

Inorganic nanoparticles (NPs) including semiconductor quantum dots (QDs), iron oxide NPs and gold NPs have been developed as contrast agents for diagnostics by molecular imaging. Compared with traditional contrast agents, NPs offer several advantages: their optical and magnetic properties can be tailored by engineering the composition, structure, size and shape; their surfaces can be modified with ligands to target specific biomarkers of disease; the contrast enhancement provided can be equivalent to millions of molecular counterparts; and they can be integrated with a combination of different functions for multimodal imaging. Here, we review recent advances in the development of contrast agents based on inorganic NPs for molecular imaging, and also touch on contrast enhancement, surface modification, tissue targeting, clearance and toxicity. As research efforts intensify, contrast agents based on inorganic NPs that are highly sensitive, target-specific and safe to use are expected to enter clinical applications in the near future.