New Class Of Contrast Agents Research Articles

Labeling Human Mesenchymal Stem Cells with Gold Nanocages for in vitro and in vivo Tracking by Two-Photon Microscopy and Photoacoustic Microscopy

Stem cell tracking is a highly important subject. Current techniques based on nanoparticle-labeling, such as magnetic resonance imaging, fluorescence microscopy, and micro-computed tomography, are plagued by limitations including relatively low sensitivity or penetration depth, involvement of ionizing irradiation, and potential cytotoxicity of the nanoparticles. Here we introduce a new class of contrast agents based on gold nanocages (AuNCs) with hollow interiors and porous walls to label human mesenchymal stem cells (hMSCs) for both in vitro and in vivo tracking using two-photon microscopy and photoacoustic microscopy. As demonstrated by the viability assay, the AuNCs showed negligible cytotoxicity under a reasonable dose, and did not alter the differentiation potential of the hMSCs into desired lineages. We were able to image the cells labeled with AuNCs in vitro for at least 28 days in culture, as well as to track the cells that homed to the tumor region in nude mice in vivo.

Recombinant high-density lipoprotein nanoparticles containing gadolinium-labeled cholesterol for morphologic and functional magnetic resonance imaging of the liver

BackgroundNatural high-density lipoproteins (HDL) possess important physiological functions to the transport of cholesterol from the peripheral tissues to the liver for metabolic degradation and excretion in the bile.Methods and resultsIn this work, we took advantage of this pathway and prepared two different gadolinium (Gd)-DTPA-labeled cholesterol-containing recombinant HDL nanoparticles (Gd-chol-HDL) and Gd-(chol)2-HDL as liver-specific magnetic resonance imaging (MRI) contrast agents. The reconstituted HDL nanoparticles had structural similarity to native HDL, and could be taken up by HepG2 cells via interaction with HDL receptors in vitro. In vivo MRI studies in rats after intravenous injections of 10 μmol gadolinium per kg of recombinant HDL nanoparticles indicated that both nanoparticles could provide signal enhancement in the liver and related organs. However, different T1-weighted image details suggested that they participated in different cholesterol metabolism and excretion pathways in the liver.ConclusionSuch information could be highly useful to differentiate functional changes as well as anatomic differences in the liver. These cholesterol-derived contrast agents and their recombinant HDL preparations may warrant further development as a new class of contrast agents for MRI of the liver and related organs.

Gold nanocages as contrast agents for photoacoustic imaging.

Gold nanoparticles with tunable absorption and scattering properties have been developed as contrast agents for various optical imaging techniques. As a hybrid modality that combines the merits of both optical and ultrasonic imaging, photoacoustic (PA) imaging also benefits from the use of these nanoparticles to greatly enhance the contrast for visualization of structures and biomarkers in biological tissues. Gold nanocages characterized by hollow interiors, ultrathin and porous walls are of particular interest for in vivo PA imaging because of their compact sizes, bio-inertness and well-defined surface chemistry, as well as their strong and highly wavelength-tunable optical absorption in the near-infrared (NIR) optical window of soft tissues. This review discusses the application of gold nanocages as a new class of contrast agents for PA imaging in the context of cancer diagnosis.

Coupled contrast for photoacoustic imaging and detection.

Nanoparticle agents with high optical absorption in the near infrared have been used to target diseased cells and increase specific contrast in photoacoustic (PA) imaging. However, background signals from tissue can severely limit the specificity of these agents. This is especially problematic for detecting targeted cells circulating in the vasculature where the large PA signal from blood can completely mask the contrast agent signal. For sensitive detection of targeted cells in the vasculature, their PA signal must be greatly enhanced compared to the blood background. Using a new class of contrast agents called coupled particles, we have developed technologies that can potentially accumulate and concentrate targeted cells while simultaneously enhancing their specific contrast compared to background signals. This approach leverages the high optical absorption and magnetic properties of Au-shell-encapsulated magnetic nanoparticles. By manipulating these coupled particles with an applied magnetic field, targets can be accumulated within the flow field and differentiated photoacoustically through motion processing algorithms providing high contrast specificity. In this talk we will discuss the basic coupled agent technology, procedures for manipulating these agents for cellular accumulation and differentiation, and challenges remaining to translate this technology into clinical use.

Probing Cytotoxicity of Gadolinium Hydroxide Nanostructures

Gadolinium hydroxide, Gd(OH)(3), nanostructures were examined for their possible use in imaging and tracking of cells and tissues by investigating their cellular interactions and cytotoxic behaviors. For this purpose, Gd(OH)(3) nanorods (length, several hundred nanometers; diameter, approximately 40 nm) and spherical nanoparticles (average diameter, <10 nm) were synthesized by solvothermal decomposition of gadolinium containing molecular precursors. After comprehensive characterization of material properties, human colon adenocarcinoma (Caco2) and human lung epithelial (A549) cells were incubated with Gd(OH)(3) nanostructures in concentrations up to 900 microg/mL to perform cytotoxicity assays (BrdU (5-bromo-2'-deoxyuridine), WST-1 (4-[3-(4-iodophenyl)-2-(4-nitrophenyl)-2H-5-tetrazolio]-1,3-benzol-disulfonate)) and living/dead staining. As observed in all in vitro assays, the investigated Gd(OH)(3) nanostructures do not induce any significant cytotoxic effect, making them promising candidates for a new class of contrast agents, which may overcome the limitations of organic stains such as photobleaching and single usage.

Iodinated Nanoscale Coordination Polymers as Potential Contrast Agents for Computed Tomography

Nanoscale coordination polymers (NCPs), prepared with metal ions and an iodinated ligand, were synthesized using reverse-phase microemulsion techniques and rapid precipitation procedures. The NCPs carry high payloads of iodine (ca. 63 wt %) and have potential applications as a new class of contrast agents for computed tomography (CT), as demonstrated by phantom studies (see figure). Detailed facts of importance to specialist readers are published as ”Supporting Information”. Such documents are peer-reviewed, but not copy-edited or typeset. They are made available as submitted by the authors. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Synthesis and evaluation of lanthanide ion DOTA–tetraamide complexes bearing peripheral hydroxyl groups

The use of lanthanide-based contrast agents for magnetic resonance imaging has become an integral component of this important diagnostic modality. These inert chelates typically possess high thermodynamic stability constants that serve as a predictor for in vivo stability and low toxicity. Recently, a new class of contrast agents was reported having a significantly lower degree of thermodynamic stability while exhibiting biodistribution profiles indicative of high stability under biological conditions. These observations are suggestive that the nature of contrast agent stability is also dependent upon the kinetics of complex dissociation, a feature of potential importance when contemplating the design of new chelates for in vivo use. We present a study of the kinetics of acid-catalyzed dissociation, thermodynamic stability, serum stability, and biodistribution of a series of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-tetraamide complexes that have been substituted with peripheral hydroxyl groups. The data indicate that these nontraditional contrast agents exhibit in vivo stability comparable to that of agents with much higher log K (ML) values, demonstrating the important contribution of kinetic inertness.

Plasmon-enhanced fluorescence of dye molecules

Enhanced fluorescence from Rhodamine 6G (R6G) mixed with gold colloids has been observed. We used fluorescence microscopy to correlate the fluorescence intensity of the dyes with the localized surface plasmon resonance (LSPR) spectra of the gold nanoparticles to which they are attached. Spectroscopic studies show that a 2.8-fold amplification of the fluorescence signal in presence of colloidal Au nanoparticles (GNP) was observed in resonance with plasmons. Such fluorophore–metal complex presents a unique opportunity for developing a new class of contrast agents for optical imaging and fluorescence based sensing, having a great potential for applications in the fields of medical diagnostics and biotechnology.

Enhanced ferrite nanoparticles as MRI contrast agents

Enhanced ferrite nanoparticles are a new class of contrast agents for magnetic resonance imaging (MRI). The enhanced ferrites are synthesized by reverse micelles technique to form iron core and oxide or ferrite shell preventing further oxidation of the nanoparticles. The nanoparticles are further functionalized using dopamine and PEG-600 to increase the solubility of the high magnetic moment nanoparticles. 1H relaxation measurements of aqueous solutions of the nanoparticles were conducted at 2.4 T. The relaxivities r 1 and r 2, representing the slopes of these curves, are 7.19 and 9.96 s −1 mM −1, respectively. These values should be compared with relaxivities of 4–5 s −1 mM −1 corresponding to commonly used commercial contrast agents in human MR examinations.

Gold Nanocages: Bioconjugation and Their Potential Use as Optical Imaging Contrast Agents

Gold nanocages of <40 nm in dimension have been synthesized using the galvanic replacement reaction between Ag nanocubes and HAuCl4 in an aqueous solution. By controlling the molar ratio between Ag and HAuCl4, the gold nanocages could be tuned to display surface plasmon resonance peaks around 800 nm, a wavelength commonly used in optical coherence tomography (OCT) imaging. OCT measurements on phantom samples indicate that these gold nanocages have a moderate scattering cross-section of approximately 8.10 x 10(-16) m2 but a very large absorption cross-section of approximately 7.26 x 10(-15) m2, suggesting their potential use as a new class of contrast agents for optical imaging. When bioconjugated with antibodies, the gold nanocages have also been demonstrated for specific targeting of breast cancer cells.

Paramagnetic lanthanide(III) complexes as pH-sensitive chemical exchange saturation transfer (CEST) contrast agents for MRI applications.

The recently introduced new class of contrast agents (CAs) based on chemical exchange saturation transfer (CEST) may have a huge potential for the development of novel applications in the field of MRI. In this work we explored the CEST properties of a series of Lanthanide(III) complexes (Ln = Eu, Dy, Ho, Er, Tm, Yb) with the macrocyclic DOTAM-Gly ligand, which is the tetraglycineamide derivative of DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid). These complexes possess two pools of exchangeable protons represented by the coordinated water and the amide protons. Yb-DOTAM-Gly displays the most interesting CEST properties when its amide N-H resonance (16 ppm upfield H2O signal) is irradiated. Up to 70% suppression of the water signal is obtained at pH 8. As the exchange rate of amide protons is base-catalyzed, Yb-DOTAM-Gly results to be an efficient pH-responsive probe in the 5.5-8.1 pH range. Moreover, a ratiometric method has been set up in order to remove the dependence of the observed pH responsiveness from the absolute concentration of the paramagnetic agent. In fact, the use of a mixture of Eu-DOTAM-Gly and Yb-DOTAM-Gly, whose exchangeable proton pools are represented by the coordinated water (ca. 40 ppm downfield H2O signal at 312K) and amide protons, respectively, produces a pH-dependent CEST effect which is the function of the concentration ratio of the two complexes.

MR Lymphangiography for Detection of Minimal Nodal Disease in Patients with Prostate Cancer

As prostate cancer is the second leading cause of cancer death in men in the USA, the clinical challenge is to develop methods that allow early diagnosis, accurate staging and precise treatment. Metastases to local and distant lymph nodes play a major role in the choice of therapy and in predicting outcome of these patients ( 1 Wilkinson BA Hamdy FC State-of-the-art staging in prostate cancer. BJU International. 2001; 87: 423-430 Crossref PubMed Google Scholar ). Clinical examination to detect lymph node metastases alone is inadequate and surgical dissection and serial histologic examinations are currently accepted “yardsticks”. In the past years, there has been debate about the pros and cons of total lymph node resection, particularly because of its morbidity, lengthiness of the surgical procedure and the resources necessary for complete pathologic evaluation of harvested nodes ( 2 Paul DB Loening SA Narayana AS Culp DA Morbidity from pelvic lymphadenectomy in staging carcinoma of the prostate. J Urol. 1983; 129: 1141-1144 Abstract Full Text PDF PubMed Scopus (71) Google Scholar ). Non-invasive imaging techniques for the detection of lymph node metastases would be of great help and a potential cost savings (imaging study vs. surgical lymphadenectomy) in the evaluation and re-staging of cancer patients. All current cross sectional imaging techniques (US, CT and MRI) have a relatively low sensitivity in detecting nodal metastases primarily because detection relies on insensitive size criteria (>10 mm short axis) ( 3 Rorvik J Halvorsen O Espeland A Haukaas S Inability of refined CT to assess local extent of prostatic cancer. Acta Radiol. 1993; : 39-42 Crossref PubMed Google Scholar ). Ultrasmall superparamagnetic iron oxide (USPIO) is a relatively new RES targeted MR contrast agent that is known for lymph node uptake ( 4 Anzai Y McLachlan S Morris M Saxton R Lufkin R Dextran-coated superparamagnetic iron oxide, an MR contrast agent for assessing lymph nodes in the head and neck. AJNR Am J Neuroradiol. 1994; 15: 87-94 PubMed Google Scholar , 5 Anzai Y Prince M Iron oxide-enhanced MR lymphography: the evaluation of cervical lymph node metastases in head and neck cancer. J Magn Reson Imaging. 1997; 7: 75-81 Crossref PubMed Scopus (86) Google Scholar , 6 Harisinghani M Saini S Slater G Schnall M Rifkin M MR imaging of pelvic lymph nodes in primary pelvic cancer with USPIO (Combidex). 1997 Contrast Medical Research Conference. Acad Radiol, Kyoto, Japan1997 Google Scholar , 7 Harisinghani MG Saini S Weissleder R et al. MR lymphangiography using ultrasmall superparamagnetic iron oxide in patients with primary abdominal and pelvic malignancies: radiographic-pathologic correlation. AJR Am J Roentgenol. 1999; 172: 1347-1351 Crossref PubMed Scopus (154) Google Scholar , 8 Harisinghani MG Saini S Hahn PF Weissleder R Mueller PR MR imaging of lymph nodes in patients with primary abdominal and pelvic malignancies using ultrasmall superparamagnetic iron oxide (Combidex). Acad Radiol. 1998; 5 (discussion S183–164): S167-169 Abstract Full Text PDF PubMed Google Scholar , 9 Bellin MF Roy C Kinkel K et al. Lymph node metastases: safety and effectiveness of MR imaging with ultrasmall superparamagnetic iron oxide particles—initial clinical experience. Radiology. 1998; 207: 799-808 PubMed Google Scholar , 10 Bellin R, Kinkel K, Challier E, et al. MR lymphography with ultrasmall iron oxide particles in patients with urologic and pelvic cancer. European Congress of Radiology. Vienna, 1997 Google Scholar , 11 Weissleder R Elizondo G Wittenberg J Lee A Josephson L Brady T Ultrasmall superparamagnetic iron oxide: an intravenous contrast agent for assesing lymph nodes with MR imaging. Radiology. 1990; 175: 494-498 PubMed Google Scholar , 12 Weissleder R Heautot J Schaefer B et al. MR lymphography: Study of a high-efficiency lymphotrophic agent. Radiology. 1994; 191: 225-230 PubMed Google Scholar , 13 Weissleder R Elizondo G Wittenberg J Rabito C Bengele H Josephson L Ultrasmall superparamagnetic iron oxide: Characterization of a new class of contrast agents for MR imaging. Radiology. 1990; 175: 489-493 PubMed Google Scholar ). The purpose of this study was to evaluate the utility of USPIO (Combidex™ Sinerem®) induced signal intensity changes in lymph nodes for staging patients with prostate cancer. Also assessed was the utility of postcontrast images alone in characterizing lymph nodes.

Safety of the Galactose–Based Ultrasound Contrast Agent Levovist

The introduction of microbubble suspensions represents a new class of contrast agents for enhancement of vascular imaging in ultrasound. The effective ingredients of this class of contrast agents are acoustically active and produce micrometer-sized inhomogeneities in the blood pool. The microbubbles interact with the sound field either by scattering the incident sound beam or by oscillations that produce resonance, which at higher acoustic power can lead to the destruction of the microbubbles. Different processing of the various microbubble echo responses led to a number of new imaging modes that exhibit varying sensitivity and specificity for microbubble detection, of which the nonlinear scatter during destruction (“stimulated acoustic emission”) is the most sensitive, enabling the detection of a single microbubble in a capillary bed. With these techniques, the visualization of organ perfusion with ultrasound became possible. These agents are characterized not only by their physicochemical uniqueness but also by their unique pharmaceutical properties. All microbubble contrast agents can be considered to be “particulates,” which, by nature of their size, remain in the blood pool until the gas is dissolved or until they are sequestered by the reticulendothelial system (RES). Their character as blood pool agents makes them ideally suited for enhancing vascular imaging. The galactose–based agent Levovist (Schering AG, Berlin, Germany) was the first microbubble agent to enter the market with sufficient stability to provide enhancement of the total body blood pool following intravenous (IV) injection. Due to the particulate character, the risk profile of this new class of agents differs from contrast agents for x-ray or magnetic resonance imaging (MRI). The theoretical risks are generated by the tolerance of the tracer medium, its osmolality, the microbubble shell material, and the microbubble particles themselves. Gas bubbles may grow either by coalescence or by inward diffusion of gases, potentially occluding small vessels in the lung and periphery. In addition, microbubbles provide a theoretical nidus for cavitation. The purpose of this article is to report the broader experience in clinical routine as regards the safety of this new class of contrast agents.

Field strength and dose dependence of contrast enhancement by gadolinium-based MR contrast agents.

The relaxivities r1 and r2 of magnetic resonance contrast agents and the T1 relaxation time values of tissues are strongly field dependent. We present quantitative data and simulations of different gadolinium-based extracellular fluid contrast agents and the modulation of their contrast enhancement by the magnetic field to be able to answer the following questions: How are the dose and field dependences of their contrast enhancement? Is there an interrelationship between dose and field dependence? Should one increase or decrease doses at specific fields? Nuclear magnetic relaxation dispersion data were acquired for the following contrast agents: gadopentetate dimeglumine, gadoterate meglumine, gadodiamide injection, and gadoteridol injection, as well as for several normal and pathological human tissue samples. The magnetic field range stretched from 0.0002 to 4.7 T, including the entire clinical imaging range. The data acquired were then fitted with the appropriate theoretical models. The combination of the diamagnetic relaxation rates (R1 = 1/T1 and R2 = 1/T2) of tissues with the respective paramagnetic contributions of the contrast agents allowed the prediction of image contrast at any magnetic field. The results revealed a nearly identical field and dose-dependent increase of contrast enhancement induced by these contrast agents within a certain dose range. The target tissue concentration (TTC) was an important though nonlinear factor for enhancement. The currently recommended dose of 0.1 mmol/kg body weight seems to be a compromise close to the lower limits of diagnostically sufficient contrast enhancement for clinical imaging at all field strengths. At low field contrast enhancement might be insufficient. Adjustment of dose or concentration, or a new class of contrast agents with optimized relaxivity, would be a valuable contribution to a better diagnostic yield of contrast enhancement at all fields.

New magnetic resonance imaging techniques for the detection of breast cancer.

The importance of contrast agents in enhancing diagnoses from magnetic resonance images has been established in numerous cases. However, the development of a potent tissue-specific contrast agent, as a sensitive probe for early detection and investigation of the physiological characteristics of a tumor, has not yet been realized in MR imaging (MRI). In nuclear scintigraphy the technique has been demonstrated; however, the poor spacial resolution inherent to the modality and the substantial dose of radioactivity administered to the patient has hindered its widespread use. This article will review the different classes of contrast agents in MRI, with special focus on the strategies involved in the development of targeted tissue-specific MRI contrast agents for the early detection of breast cancer. The features of a new class of contrast agents for targeted MR imaging will be described. Gadolinium-containing melanin polymers (GMP's) have been synthesized as MR contrast agents in our laboratory. These GMP's demonstrate significantly higher relaxivities than any other paramagnetic contrast agents reported; consequently, they are extremely effective contrast enhancing, imaging agents by themselves. The successful coupling of these potent GMP's to a monoclonal antibody specific for breast carcinoma, the 323/A3 monoclonal antibody, suggests that in vivo tissue-specific MR imaging, at the receptor level, will become feasible in the near future.

Ultrasmall superparamagnetic iron oxide: characterization of a new class of contrast agents for MR imaging.

An ultrasmall superparamagnetic iron oxide (USPIO) preparation was developed that is small enough to migrate across the capillary wall, a prerequisite in the design of targetable particulate pharmaceuticals. Seventy percent of particles were smaller than 10 nm; 26%, smaller than 5 nm. The blood half-life of USPIO in rats was 81 minutes, considerably longer than that of larger superparamagnetic iron oxide preparations such as AMI-25 (6 minutes). Electron microscopy demonstrated that USPIO particles transmigrate the capillary wall by means of vesicular transport and through interendothelial junctions. Twenty-four hours after intravenous administration, 3.6% of the injected dose per gram of tissue was found in lymph nodes, 2.9% per gram in bone marrow, 6.3% per gram in liver, and 7.1% per gram in spleen. The major potential applications for USPIO are as (a) an intravenous contrast agent for the lymphatic system, (b) a bone marrow contrast agent, (c) a long-half-life perfusion agent for brain and heart, and (d) the magnetic moiety in organ-targeted superparamagnetic contrast agents for magnetic resonance imaging.

A new class of contrast agents for magnetic resonance imaging based on selective reduction of water-T2 by chemical exchange.

Compounds containing mobile protons can act as contrast agents by increasing the value of the term (1/12 - 1/11). The efficiency of this method is markedly pH- and field-dependent. There are many such compounds allowing a choice to be made based on the characteristics of the tissue or organ, magnetic field strength, and solution pH levels. The properties of some of these chemicals have been investigated at different magnetic field strength and solution pH levels. The authors report herein the properties of iopamidol a well-known x-ray contrast agent, and stress its potential effect as an MRI contrast agent. The influence on the T2 decrease of the chemical shift separation delta omega (in frequency units) between water and exchangeable proton of the contrast agent may be increased by adding suitable shift reagents which interact with basic sites close to the protons involved in the chemical exchange.

A New Class of Contrast Agents for Magnetic Resonance Imaging Based on Selective Reduction of Water-T2 by Chemical Exchange

A New Class of Contrast Agents for Magnetic Resonance Imaging Based on Selective Reduction of Water-T2 by Chemical Exchange

Ferrite particles for bowel contrast in MR imaging: design issues and feasibility studies.

Diverse materials with varying physical and magnetic properties have been evaluated as gastrointestinal contrast agents for magnetic resonance (MR) imaging. Uniform marking of the small bowel remains the greatest challenge. Ferrites are magnetically active iron oxide particles that are miscible with water and cause loss of signal on MR images. The decrease in MR signal intensity produced by ferrites occurs with a wide range of iron concentrations (0.1-10 mM) and with both T1- and T2-weighted pulse sequences. These effects of ferrites are explained by predominant T2 shortening with negligible T1 effects. The ferrite preparation used in this study was stable in vitro, with little iron solubilized by acid. Intragastric administration of ferrite (5 mg of iron per kg in 6 ml) routinely marked the small bowel of rats. The authors conclude that ferrites represent a promising new class of contrast agents for gastrointestinal MR imaging.

The non-ionic dimers: a new class of contrast agents.

Non-ionic dimers are a new class of iodinated radiological contrast agents. Some physico-chemical and pharmacological properties of three representative compounds are presented. Non-ionic dimers are iso-osmolar with plasma at all iodine concentrations unless diluted with saline and in terms of chemotoxicity they appear to be closely comparable with the established non-ionic monomeric agents. It is shown that the data lend support to the theory that it is the degree of steric hindrance of the hydrophobic iodine atoms by side-chains which determines this chemotoxicity. Areas in which agents of this type may find applications are indicated.