Generation Of Contrast Agents Research Articles

Unveiling the next generation of MRI contrast agents: current insights and perspectives on ferumoxytol-enhanced MRI.

Contrast-enhanced magnetic resonance imaging (CE-MRI) is a pivotal tool for global disease diagnosis and management. Since its clinical availability in 2009, the off-label use of ferumoxytol for ferumoxytol-enhanced MRI (FE-MRI) has significantly reshaped CE-MRI practices. Unlike MRI that is enhanced by gadolinium-based contrast agents, FE-MRI offers advantages such as reduced contrast agent dosage, extended imaging windows, no nephrotoxicity, higher MRI time efficiency and the capability for molecular imaging. As a leading superparamagnetic iron oxide contrast agent, ferumoxytol is heralded as the next generation of contrast agents. This review delineates the pivotal clinical applications and inherent technical superiority of FE-MRI, providing an avant-garde medical-engineering interdisciplinary lens, thus bridging the gap between clinical demands and engineering innovations. Concurrently, we spotlight the emerging imaging themes and new technical breakthroughs. Lastly, we share our own insights on the potential trajectory of FE-MRI, shedding light on its future within the medical imaging realm.

Contrast-Enhanced Ultrasound in the Diagnosis of Ocular Pathology: Application Prospects

Contrast-enhanced ultrasound is a highly informative method for the differential diagnosis of focal changes in various organs and tissues, which allows to visualize vascular structures and obtain new previously unavailable information when using standard b-scan. At the beginning of the 21st century after the development of a new generation of contrast agents consisting of microbubbles with inert gas contrast-enhanced ultrasound became widely used to improve visual assessment of small-caliber vessels in the diagnosis of the abdominal cavity and retroperitoneal space pathology: benign and malignant liver formations, spleen pathology, inflammatory diseases and tumors of the pancreas, defects in renal perfusion, tumor and cystic lesions of the kidneys. Assessment of intraocular tumors microcirculation and diagnosis of vitreoretinal pathology are still two main directions of using contrast-enhanced ultrasound in ophthalmology. In recent years, there has been a growing interest in the use of contrast-enhanced ultrasound in the study of perfusion of different types of uveal melanoma in an animal experiment. A promising direction in the field of genetic engineering is the use of local contrast-enhanced ultrasound exposure on retinal cells (retinal ganglion cells, retinal pigment epithelium) to promote gene transfection (non-viral nucleic acid delivery into the DNA of a cell), which is an important part of gene therapy. Despite the successes achieved in the study of contrast-enhanced ultrasound effectiveness in medicine, further research is needed to increase the informative value of this method in the diagnosis of ophthalmopathology.

Laser-driven resonance of light-absorbing ultrasound contrast microbubbles

The sensitivity of ultrasound imaging is greatly enhanced by the use of microbubble contrast agents through resonant volumetric oscillations. While the increased acoustic contrast is of prime interest for perfusion imaging of organs, microbubbles until now have limited benefit in terms of specificity for ultrasound imaging. Original strategies are required to tackle this difficulty that rely on loading functional targeting ligands onto the microbubble encapsulation. In parallel, laser light offers great specificity in its interaction with tissue. This advantage is put to use in photoacoustic imaging where absorbed laser light is converted into a measurable acoustic signal. Here, we present a novel ultrasound contrast agent designed to make use of the specificity of laser light. The acoustic agent consists of a gas core encapsulated by an oil layer containing an absorbing dye. The resulting laser light absorption can then be used to heat up the gas and drive the system into resonance, thereby generating ultrasound. Combining finite difference simulations and ultra high-speed imaging led to a quantitative physical description of the optical and thermal interactions in the system resulting in the efficient generation of acoustic waves in the MHz range. A range of physical bubble parameters are investigated, i.e., thickness and composition of the light absorbing oil layer. This new generation of contrast agents will open up new applications in medical diagnostic and therapeutic imaging.

Design of functionalized gold nanoparticle probes for computed tomography imaging.

The development of new molecules able to efficiently act as long-circulating computed tomography (CT) contrast agents is one of the most crucial topics in the biomedical field. In the last years, the chance to manipulate materials at the nano-size level gave new boost to this research, with the specific aim to design innovative nanoprobes. Gold nanoparticles (AuNPs) have showed unique X-rays attenuation properties which, combined with their easy surface functionalization, makes them ideal candidates for the next generation of contrast agents. In this paper, we present a rational and facile approach to synthesize engineered and water-stable AuNPs, achieving concentrated colloidal solution with high Hounsfield Units (HU). An accurate control of reagents ratio allowed us to design AuNPs with different shapes, from symmetrical to anisotropic morphology, in a convenient 'one-pot' fashion. Their activity as efficient and reliable CT contrast agents has been evaluated and compared. Moreover, glucosamine-functionalized gold nanoparticles have been developed ([Au] = 31.20 mg/mL; HU = 2453), in order to obtain a CT contrast agent able to combine spatial resolution with metabolic information. Copyright © 2016 John Wiley & Sons, Ltd.

ChemInform Abstract: Recent Advances in Upconversion Nanoparticles‐Based Multifunctional Nanocomposites for Combined Cancer Therapy

AbstractReview: [85 refs.

Chemical design of nanoprobes for T1-weighted magnetic resonance imaging

Magnetic resonance imaging (MRI), which offers a number of advantages such as unlimited tissue penetration, zero ionizing radiation, and a noninvasive nature, has received considerable attention over the past two decades as a technique for clinical diagnosis. To improve imaging sensitivity, contrast agents have been employed to accelerate the relaxation rate of water molecules and thus to increase the contrast between specific tissues or organs of interest. However, conventional contrast agents such as Gd3+-based T1 complexes and iron oxide nanoparticle-based T2 contrast agents have been proven to have adverse effects. The former may cause fatal nephrogenic systemic fibrosis (NSF) and difficulty in metabolism, while the latter is less sensitive due to the background interference. Also, their development has been well documented. Therefore, the orientation of this review will be geared toward the newly developed nanoparticulate agents that serve as better alternatives. In this regard, the recent advances on various nanostructured Mn/Fe-based T1 contrast agents seem to fit these categories. As they reveal longer circulation half-life and better biocompatibility, they have demonstrated themselves as a promising T1 candidate for MRI. The focus of this review will be on the preparation and fabrication of T1 contrast agents that contain mainly paramagnetic manganese and iron ions, with special attention being paid to the growth mechanism. Additional emphasis is also put on their progressive development in an aim to overcome the drawbacks of classical iron oxide nanoparticle-based T2 and Gd3+-based T1 contrast agents. Representative applications in vitro and in vivo will be presented for this new generation of contrast agents. The pros and cons of each case are also briefly summarized.

Recent Advances in Upconversion Nanoparticles-Based Multifunctional Nanocomposites for Combined Cancer Therapy.

Lanthanide-doped upconversion nanoparticles (UCNPs) have the ability to generate ultraviolet or visible emissions under continuous-wave near-infrared (NIR) excitation. Utilizing this special luminescence property, UCNPs are approved as a new generation of contrast agents in optical imaging with deep tissue-penetration ability and high signal-to-noise ratio. The integration of UCNPs with other functional moieties can endow them with highly enriched functionalities for imaging-guided cancer therapy, which makes composites based on UCNPs emerge as a new class of theranostic agents in biomedicine. Here, recent progress in combined cancer therapy using functional nanocomposites based on UCNPs is reviewed. Combined therapy referring to the co-delivery of two or more therapeutic agents or a combination of different treatments is becoming more popular in clinical treatment of cancer because it generates synergistic anti-cancer effects, reduces individual drug-related toxicity and suppresses multi-drug resistance through different mechanisms of action. Here, the recent advances of combined therapy contributed by UCNPs-based nanocomposites on two main branches are reviewed: i) photodynamic therapy and ii) chemotherapy, which are the two most widely adopted therapies of UCNPs-based composites. The future prospects and challenges in this emerging field will be also discussed.

Virus-based nanomaterials as positron emission tomography and magnetic resonance contrast agents: from technology development to translational medicine.

Viruses have recently emerged as ideal protein scaffolds for a new class of contrast agents that can be used in medical imaging procedures such as positron emission tomography (PET) and magnetic resonance imaging (MRI). Whereas synthetic nanoparticles are difficult to produce as homogeneous formulations due to the inherently stochastic nature of the synthesis process, virus-based nanoparticles are genetically encoded and are therefore produced as homogeneous and monodisperse preparations with a high degree of quality control. Because the virus capsids have a defined chemical structure that has evolved to carry cargoes of nucleic acids, they can be modified to carry precisely defined cargoes of contrast agents and can be decorated with spatially defined contrast reagents on the internal or external surfaces. Viral nanoparticles can also be genetically programed or conjugated with targeting ligands to deliver contrast agents to specific cells, and the natural biocompatibility of viruses means that they are cleared rapidly from the body. Nanoparticles based on bacteriophages and plant viruses are safe for use in humans and can be produced inexpensively in large quantities as self-assembling recombinant proteins. Based on these considerations, a new generation of contrast agents has been developed using bacteriophages and plant viruses as scaffolds to carry positron-emitting radioisotopes such as [(18) F] fluorodeoxyglucose for PET imaging and iron oxide or Gd(3+) for MRI. Although challenges such as immunogenicity, loading efficiency, and regulatory compliance remain to be address, virus-based nanoparticles represent a promising new enabling technology for a new generation of highly biocompatible and biodegradable targeted imaging reagents.

Ultrasonic propagation in suspensions of encapsulated compressible nanoparticles

Dispersion and absorption are examined for dilute suspensions of encapsulated droplets of nanometric size, with typical radii around 100 nm. This new generation of contrast agents is designed for targeted delivery of drugs. Compared to standard contrast agents used for imaging, particles are of smaller size to pass the endothelial barrier, their shell made up of biocompatible material is stiffer to undergo a longer time life and they have a liquid (PFC) instead of a gaseous core. Ultrasound propagation of these suspensions is modeled by combining (i) a dilatational mode of oscillation assuming a compressible shell with a visco-elastic behavior of Kelvin-Voigt or Maxwell type (relaxation), (ii) a translational mode of oscillation induced by visco-inertial interaction with the ambient fluid, and (iii) polydispersion in terms of radius and shell thickness. Influence of the various effects will be examined. Experimental measurements of the dispersion and absorption properties of nanodroplets solutions over the 1–100 MHz frequency range are performed for various temperatures and concentrations. They allow to fit with good accuracy the model properties and estimate some unknown mechanical properties of the shell of the nanodroplets. [Work supported by programme Emergence-UPMC—project NACUNAT and by Inserm/Plan Cancer—project NABUCCO.]

Gd-based Macromolecules and Nanoparticles as Magnetic Resonance Contrast Agents for Molecular Imaging

As we move towards an era of personalized medicine, molecular imaging contrast agents are likely to see an increasing presence in routine clinical practice. Magnetic resonance (MR) imaging has garnered particular interest as a platform for molecular imaging applications due its ability to monitor anatomical changes concomitant with physiologic and molecular changes. One promising new direction in the development of MR contrast agents involves the labeling and/or loading of nanoparticles with gadolinium (Gd). These nanoplatforms are capable of carrying large payloads of Gd, thus providing the requisite sensitivity to detect molecular signatures within disease pathologies. In this review, we discuss some of the progress that has recently been made in the development of Gd-based macromolecules and nanoparticles and outline some of the physical and chemical properties that will be important to incorporate into the next generation of contrast agents, including high Gd chelate stability, high "relaxivity per particle" and "relaxivity density", and biodegradability.

Advances in Metal-Based Probes for MR Molecular Imaging Applications

The role of MRI in the armory of diagnostic modalities for the medicine of the forthcoming years largely depends on how chemistry will provide advanced tools to meet the medical needs. This review aims at outlining the most innovative approaches that have been undertaken in the recent history of MRI contrast agents for tackling the challenges of sensitivity and specificity required by the new generation of contrast agents that should allow the visualization of pathological processes occurring on cellular and molecular scale (the so-called Molecular Imaging). Most of the classes of MRI agents clinically approved or currently under investigation in a preclinical phase exploit peculiar magnetic properties of metals. The conventional agents acting as T(1) or T(2)/T(2)* relaxation enhancers are primarily based on the paramagnetic or the superparamagnetic properties of Gd(III)-, Mn(II)- and iron oxides systems. Recently, there has been a renewed interest towards paramagnetic lanthanide complexes with an anisotropic electronic configuration thanks to their ability to induce strong effect on the resonance frequency of the spins dipolarly coupled with them. Such systems, formerly mainly used as shift reagents, have now attracted much attention in the emerging field of Chemical Exchange Saturation Transfer (CEST) MRI agents.

Cell-Penetrating Peptides and Peptide Nucleic Acid-Coupled MRI Contrast Agents: Evaluation of Cellular Delivery and Target Binding

Molecular imaging of cells and cellular processes can be achieved by tagging intracellular targets such as receptors, enzymes, or mRNA. Seeking to visualize the presence of specific mRNAs by magnetic resonance (MR) imaging, we coupled peptide nucleic acids (PNA) with gadolinium-based MR contrast agents using cell-penetrating peptides for intracellular delivery. Antisense to mRNA of DsRed2 protein was used as proof of principle. The conjugates were produced by continuous solid-phase synthesis followed by chelation with gadolinium. Their cellular uptake was confirmed by fluorescence microscopy and spectroscopy as well as by MR imaging of labeled cells. The cell-penetrating peptide D-Tat(57-49) was selected over two other derivatives of HIV-1 Tat peptide, based on its superior intracellular delivery of the gadolinium-based contrast agents. Further improved delivery of conjugates was achieved upon coupling peptide nucleic acids (antisense to mRNA of DsRed2 protein and nonsense with no natural counterpart). Significant enhancement in MR contrast was obtained in cells labeled with concentrations as low as 2.5 μM of these agents. Specific binding of the targeting PNA containing conjugate to its complementary oligonucleotide sequence was proven by in vitro cell-free assay. In contrast, a lack of specific enrichment was observed in transgenic cells containing the target due to nonspecific vesicular entrapment of contrast agents. Preliminary biodistribution studies showed conjugate-related fluorescence in several organs, especially the liver and bladder, indicating high mobility of the agent in spite of its high molecular weight. No conjugate related toxicity was observed. These results are encouraging, as they warrant further molecular optimization and consecutive specificity studies in vivo of this new generation of contrast agents.

Application of semiconductor and metal nanostructures in biology and medicine

Advances in nanotechnology research have led to the creation of new generation of contrast agents, therapeutics, and delivery systems. These applications are expected to significantly improve the diagnosis and treatment of a variety of diseases. Two nanotechnologies-semiconductor and metallic nanostructures-are the most advanced in this young field and have been extensively investigated for clinical use. These nanostructures are currently the "model" for the developments of many novel nanostructures. This review describes their chemical design, tunable properties, and utility in medicine. Furthermore, we will describe the current understanding of their toxicity, which could be barriers to their use for human.

Bubble dynamics involved in ultrasonic imaging

In clinical ultrasound, blood cells cannot be differentiated from surrounding tissue, due to the low acoustic impedance difference between blood cells and their surroundings. Resonant gas bubbles introduced in the bloodstream are ideal markers, if rapid dissolution can be prevented. Ultrasound contrast agents consist of microscopically small bubbles encapsulated by an elastic shell. These microbubbles oscillate upon ultrasound insonification. Microbubbles with thin lipid shells have demonstrated highly nonlinear behavior. To enhance diagnostic ultrasound imaging techniques and to explore therapeutic applications, these medical microbubbles have been modeled. Several detection techniques have been proposed to improve the detectability of the microbubbles. A new generation of contrast agents, with special targeting ligands attached to the shells, may assist the imaging of nonphysical properties of target tissue. Owing to microbubble-based contrast agents, ultrasound is becoming an even more important technique in clinical diagnostics.

Physical properties of ultrasound contrast agents

It has recently been shown that the new generation of contrast agents has suitable pressure ranges and driving pulse sequences for optimal imaging. Differences in imaging conditions are due to differences in physical properties of microbubbles of the ultrasound contrast agents: mechanical properties of shell materials and diffusion of encapsulated gases. In this study, bubble behaviors of two types of contrast agents were observed using a high-speed camera, and differences in mechanical properties of the shells and diffusion of the encapsulated gases were investigated. A microbubble was exposed to five ultrasound pulses with constant or increasing pressures with a pulse interval of 20 μs, and the bubbles exposed to each pulse were photographed using a high-speed camera. Definity® and Levovist® were used in the experiments. In the case of Definity®, amplitude of bubble oscillation increased with an increase in pulse pressure. In the case of Levovist®, discontinuous expansion of the bubble was observed during exposure to five pulses with increasing pressure, and it is thought that the strong non-linear relationship between oscillation amplitude and ultrasound pressure in the case of Levovist® is caused by the presence of bubble shells, which cannot be treated with a simple elastic model. Furthermore, shrinkage of bubble fragments was observed in the case of Levovist®, and it is thought that diffusion of encapsulated gas is accelerated by exposure to pulsed ultrasound.

Ultrasound contrast agents for hepatic imaging with nonlinear modes

Curr Probl Diagn Radiol 2003;32:66.

Ultrasound contrast agents for hepatic imaging with nonlinear modes

The continuing development of nonlinear imaging, as well as a whole new generation of contrast agents, holds out great prospects in improving liver imaging. Optimization of the equipment settings for different classes of contrast agents is essential in the detection and characterization of focal liver lesions. On the basis of the preliminary results of multicenter clinical trials, it is reasonable to assume that their application in specific clinical settings will impact favorably on patient management.

Current and future contrast agents.

This article focuses on current and new contrast agents for opacification of left-sided cardiac chambers and myocardium after intravenous injection. The first generation of contrast agents, such as agitated saline, hydrogen peroxide, indocyanine green dye, and iodinated contrast, required aortic or intracoronary injection to opacify the left heart. Second generation agents, such as sonicated 5% human albumin-containing air bubbles, were capable of transpulmonary passage but often failed to produce adequate imaging of the left heart. Newer agents containing fluorocarbon gases within albumin, surfactant, lipid, or polymer shells hold great promise to achieve myocardial perfusion via intravenous injection. The characteristics of these agents and the results of early clinical trials will be discussed.

Myocardial contrast echocardiography: clinical benefit and practical issues.

Real-time bedside evaluation of myocardial perfusion after intravenous application of microbubbles is the ultimate goal for contrast echocardiography. Over the past decade rapid evolution has occurred in the development of contrast agents, ultrasound equipment tailored to their detection, and image interpretation. This article offers a review of the basic concepts of the technique's background, contrast agent design, and imaging technology. The major clinical indications of myocardial contrast echocardiography are evaluation of acute ischemic syndromes, diagnosis of viable myocardium following AMI, and the detection of CAD using stress contrast perfusion imaging. Furthermore, the article addresses the most significant practical problems and suggested solutions to master those problems. As major new achievements are realistic expectations for the first decade of the twenty-first century, we conclude that the coupling of a new generation of contrast agents with innovative echocardiographic instrumentation will ultimately enable the full potential of myocardial contrast echocardiography to be realized which may revolutionize modern echocardiography.