New Class Of Contrast Agents Research Articles

How to stop using gadolinium chelates for magnetic resonance imaging: clinical-translational experiences with ferumoxytol.

Gadolinium chelates have been used as standard contrast agents for clinical MRI for several decades. However, several investigators recently reported that rare Earth metals such as gadolinium are deposited in the brain for months or years. This is particularly concerning for children, whose developing brain is more vulnerable to exogenous toxins compared to adults. Therefore, a search is under way for alternative MR imaging biomarkers. The United States Food and Drug Administration (FDA)-approved iron supplement ferumoxytol can solve this unmet clinical need: ferumoxytol consists of iron oxide nanoparticles that can be detected with MRI and provide significant T1- and T2-signal enhancement of vessels and soft tissues. Several investigators including our research group have started to use ferumoxytol off-label as a new contrast agent for MRI. This article reviews the existing literature on the biodistribution of ferumoxytol in children and compares the diagnostic accuracy of ferumoxytol- and gadolinium-chelate-enhanced MRI. Iron oxide nanoparticles represent a promising new class of contrast agents for pediatric MRI that can be metabolized and are not deposited in the brain.

Light, sound, nanobubbles: New approach to contrast-enhanced ultrasound and photoacoustic imaging

To overcome the most significant deficiencies of conventional and contrast-enhanced ultrasound imaging—low contrast and large size of microbubbles, we introduced new class of contrast agents—nanometer scale particles that are capable of escaping vascular compartments, penetrating into tissue, and then, once they reach the target site, generating sufficient ultrasound and photoacoustic contrast upon user-controlled optical activation. These multimodal contrast agents—phase-change perfluorocarbon nanodroplets and plasmonic nanoparticles covered by azide compounds—are stable at physiological temperatures, biocompatible, and monodisperse in size. Given the unique properties of the particles, our approach to image these particles is drastically different and is based on ultrasound read-out of the optically induced temporal changes. Specifically, time-varying ultrasound signals exhibited by the nanoparticles versus the static background are used to reconstruct a high contrast, background-free image of the contrast agent. Furthermore, these particles allow for multiplexed molecular imaging by permitting user-controlled triggering of distinct color-coded populations of contrast agents via tuning of the incident laser irradiation to match peak optical absorption of the particles. Finally, nanoparticles may also contain therapeutic cargo and thus can be used for controlled drug delivery and release. This presentation, via examples, will discuss diagnostic imaging and image-guided therapy using the gas-generating nanoparticles.

Water-Mediated Nanostructures for Enhanced MRI: Impact of Water Dynamics on Relaxometric Properties of Gd-DTPA.

Recently, rational design of a new class of contrast agents (CAs), based on biopolymers (hydrogels), have received considerable attention in Magnetic Resonance Imaging (MRI) diagnostic field. Several strategies have been adopted to improve relaxivity without chemical modification of the commercial CAs, however, understanding the MRI enhancement mechanism remains a challenge.Methods: A multidisciplinary approach is used to highlight the basic principles ruling biopolymer-CA interactions in the perspective of their influence on the relaxometric properties of the CA. Changes in polymer conformation and thermodynamic interactions of CAs and polymers in aqueous solutions are detected by isothermal titration calorimetric (ITC) measurements and later, these interactions are investigated at the molecular level using NMR to better understand the involved phenomena. Water molecular dynamics of these systems is also studied using Differential Scanning Calorimetry (DSC). To observe relaxometric properties variations, we have monitored the MRI enhancement of the examined structures over all the experiments. The study of polymer-CA solutions reveals that thermodynamic interactions between biopolymers and CAs could be used to improve MRI Gd-based CA efficiency. High-Pressure Homogenization is used to obtain nanoparticles.Results: The effect of the hydration of the hydrogel structure on the relaxometric properties, called Hydrodenticity and its application to the nanomedicine field, is exploited. The explanation of this concept takes place through several key aspects underlying biopolymer-CA's interactions mediated by the water. In addition, Hydrodenticity is applied to develop Gadolinium-based polymer nanovectors with size around 200 nm with improved MRI relaxation time (10-times).Conclusions: The experimental results indicate that the entrapment of metal chelates in hydrogel nanostructures offers a versatile platform for developing different high performing CAs for disease diagnosis.

Targeted Contrast Agents for Molecular MRI

Molecular magnetic resonance imaging (MRI) provides information non-invasively at cellular and molecular levels, for both early diagnosis and monitoring therapeutic follow-up. This imaging technique requires the development of a new class of contrast agents, which signal changes (typically becomes enhanced) when in presence of the cellular or molecular process to be evaluated. Even if molecular MRI has had a prominent role in the advances in medicine over the past two decades, the large majority of the developed probes to date are still in preclinical level, or eventually in phase I or II clinical trials. The development of novel imaging probes is an emergent active research domain. This review focuses on gadolinium-based specific-targeted contrast agents, providing rational design considerations and examples of the strategies recently reported in the literature.

Bandgap Engineered Polypyrrole-Polydopamine Hybrid with Intrinsic Raman and Photoacoustic Imaging Contrasts.

Intrinsically multimodal nanomaterials have revealed their great potential as a new class of contrast agents. We herein report a bandgap engineering strategy to develop an intrinsically Raman-photoacoustic (PA) active probe that is based on semiconducting conjugated polymers. This dual modal probe is prepared by doping a semiconducting conjugated polymer with polydopamine (PDA) through a one-pot reaction. When applied in the polypyrrole (PPy), this strategy can enhance Raman scattering and the PA amplitude of PPy-PDA hybrid by 3.2 and 2.4 times, respectively, so that both signals can be further applied in bioimaging. In the hybrid, such a dual-enhancement effect is achieved by infusing these two macromolecules at the nanoscale to reduce the optical bandgap energy. This work not only introduces a dual modal contrast agent but also provides a new method of manipulating semiconducting polymer's inherent optical features for bioimaging.

Optical and Cross-Sectional Imaging Technologies for Bladder Cancer.

Optical and cross-sectional imaging plays critical roles in bladder cancer diagnostics. White light cystoscopy remains the cornerstone for the management of non-muscle-invasive bladder cancer. In the last decade, significant technological improvements have been introduced for optical imaging to address the known shortcomings of white light cystoscopy. Enhanced cystoscopy modalities such as blue light cystoscopy and narrowband imaging survey a large area of the urothelium and provide contrast enhancement to detect additional lesions and decrease cancer recurrence. However, higher false-positive rates accompany the gain of sensitivity. Optical biopsy technologies, including confocal laser endomicroscopy and optical coherence tomography, provide cellular resolutions combined with subsurface imaging, thereby enabling optical-based cancer characterization, and may lead to real-time cancer grading and staging. Coupling of fluorescently labeled binding agents with optical imaging devices may translate into high molecular specificity, thus enabling visualization and characterization of biological processes at the molecular level. For cross-sectional imaging, upper urinary tract evaluation and assessment potential extravesical tumor extension and metastases are currently the primary roles, particularly for management of muscle-invasive bladder cancer. Multi-parametric MRI, including dynamic gadolinium-enhanced and diffusion-weighted sequences, has been investigated for primary bladder tumor detection. Ultrasmall superparamagnetic particles of iron oxide (USPIO) are a new class of contrast agents that increased the accuracy of lymph node imaging. Combination of multi-parametric MRI with positron emission tomography is on the horizon to improve accuracy rates for primary tumor diagnostics as well as lymph node evaluation. As these high-resolution optical and cross-sectional technologies emerge and develop, judicious assessment and validation await for their clinical integration toward improving the overall management of bladder cancer.

PFPE-Based Polymeric 19F MRI Agents: A New Class of Contrast Agents with Outstanding Sensitivity

19F magnetic resonance imaging (MRI) is a powerful noninvasive imaging technique with demonstrated potential for the detection of important diseases. The major challenge in the design of 19F MRI agents is signal attenuation caused by the reduced solubility and segmental mobility of probes with high numbers of fluorine atoms. Careful choice of the fluorinated moiety is required to maintain image quality at the fluorine contents required for high imaging sensitivity. Here we report the synthesis of perfluoropolyether (PFPE) end-functionalized homopolymers of oligo(ethylene glycol) methyl ether acrylate (poly(OEGA)m-PFPE) as highly sensitive 19F MRI contrast agents (CAs). The structural characteristics, conformation and aggregation behavior, 19F NMR relaxation properties, and 19F MR imaging were studied in detail. Dynamic light scattering and molecular dynamics (MD) simulations were conducted and demonstrated that poly(OEGA)m-PFPE with the longest poly(OEGA)m segments (m = 20) undergoes single-chain folding ...

Antibody Conjugated, Raman Tagged Hollow Gold-Silver Nanospheres for Specific Targeting and Multimodal Dark-Field/SERS/Two Photon-FLIM Imaging of CD19(+) B Lymphoblasts.

In this Research Article, we propose a new class of contrast agents for the detection and multimodal imaging of CD19(+) cancer lymphoblasts. The agents are based on NIR responsive hollow gold-silver nanospheres conjugated with antiCD19 monoclonal antibodies and marked with Nile Blue (NB) SERS active molecules (HNS-NB-PEG-antiCD19). Proof of concept experiments on specificity of the complex for the investigated cells was achieved by transmission electron microscopy (TEM). The microspectroscopic investigations via dark field (DF), surface-enhanced Raman spectroscopy (SERS), and two-photon excited fluorescence lifetime imaging microscopy (TPE-FLIM) corroborate with TEM and demonstrate successful and preferential internalization of the antibody-nanocomplex. The combination of the microspectroscopic techniques enables contrast and sensitivity that competes with more invasive and time demanding cell imaging modalities, while depth sectioning images provide real time localization of the nanoparticles in the whole cytoplasm at the entire depth of the cells. Our findings prove that HNS-NB-PEG-antiCD19 represent a promising type of new contrast agents with great possibility of being detected by multiple, non invasive, rapid and accessible microspectroscopic techniques and real applicability for specific targeting of CD19(+) cancer cells. Such versatile nanocomplexes combine in one single platform the detection and imaging of cancer lymphoblasts by DF, SERS, and TPE-FLIM microspectroscopy.

Mn(ii) silver-aptamer clusters for targeted MR imaging of tumors.

Hypoxia-inducible factor (HIF) highly expressed in most of the cancer cells. The Mn(ii)-aptamer based nanoclusters with 3D structures would be HIF-aptamer based targeted magnetic resonance imaging agents for cancer MRI diagnosis. Herein, a new class of contrast agent Mn(ii) silver-aptamer clusters (AdpaMn@DNA-Ag-DNAG1) were constructed based on the assembly of DNA-mediated Ag nanoclusters (DNA-AgNCs) with the Mn(ii) complex (AdpaMn) and DNAG1, the recognition sequence of GLUT-1. Then, the Mn(ii) silver-aptamer clusters (AdpaMn@DNA-Ag-DNAG1) are used as the MRI agents both in vitro and in vivo. The results show that the MRI signal is clearly presented in the tumor position. Consequently, the Mn(ii) silver-aptamer clusters can be used as a new class of contrast agents for targeted MR imaging of tumors.

Iron Oxide Nanoparticles as Contrast Agents in Molecular Magnetic Resonance Imaging: Do They Open New Perspectives in Cardiovascular Imaging?

Molecular magnetic resonance imaging has recently emerged as a powerful tool for the detection and assessment of cardiovascular diseases. Contrast agents have an important role in this novel modality because molecular imaging requires highly sensitive, specific, and efficient imaging agents. Iron oxide nanoparticles (IONs) are a new class of contrast agents with unique properties that provide special opportunities in cardiovascular molecular imaging. IONs are captured by macrophages and can be successfully used in the detection and evaluation of atherosclerotic plaques, abdominal aortic aneurysms, and inflammations related to myocardial infarction. The purpose of this review is to provide a brief description of the basic characteristics of IONs, with a special focus on their role as molecular magnetic resonance imaging contrast agents and their cardiovascular applications.

New insights into lung diseases using hyperpolarized gas MRI

Hyperpolarized (HP) gases are a new class of contrast agents that permit to obtain high temporal and spatial resolution magnetic resonance images (MRIs) of the lung airspaces. HP gas MRI has become an important research tool not only for morphological and functional evaluation of normal pulmonary physiology but also for regional quantification of pathologic changes occurring in several lung diseases. The purpose of this work is to provide an introduction to MRI using HP noble gases, describing both the basic principles of the technique and the new information about lung disease provided by clinical studies with this method. The applications of the technique in normal subjects, smoking related lung disease, asthma, and cystic fibrosis are reviewed.

RM con gases hiperpolarizados: Nuevas perspectivas en el estudio de enfermedades pulmonares

Hyperpolarized (HP) gases are a new class of contrast agents that permit to obtain high temporal and spatial resolution magnetic resonance images (MRI) of the lung airspaces. HP gas MRI has become important research tool not only for morphological and functional evaluation of normal pulmonary physiology but also for regional quantification of pathologic changes occurring in several lung diseases. The purpose of this work is to provide an introduction to MRI using HP noble gases, describing both the basic principles of the technique and the new information about lung disease provided by clinical studies with this method. The applications of the technique in normal subjects, smoking related lung disease, asthma, and cystic fibrosis are reviewed.

Nanoparticles in magnetic resonance imaging: from simple to dual contrast agents.

Magnetic resonance imaging (MRI) has become one of the most widely used and powerful tools for noninvasive clinical diagnosis owing to its high degree of soft tissue contrast, spatial resolution, and depth of penetration. MRI signal intensity is related to the relaxation times (T1, spin–lattice relaxation and T2, spin–spin relaxation) of in vivo water protons. To increase contrast, various inorganic nanoparticles and complexes (the so-called contrast agents) are administered prior to the scanning. Shortening T1 and T2 increases the corresponding relaxation rates, 1/T1 and 1/T2, producing hyperintense and hypointense signals respectively in shorter times. Moreover, the signal-to-noise ratio can be improved with the acquisition of a large number of measurements. The contrast agents used are generally based on either iron oxide nanoparticles or ferrites, providing negative contrast in T2-weighted images; or complexes of lanthanide metals (mostly containing gadolinium ions), providing positive contrast in T1-weighted images. Recently, lanthanide complexes have been immobilized in nanostructured materials in order to develop a new class of contrast agents with functions including blood-pool and organ (or tumor) targeting. Meanwhile, to overcome the limitations of individual imaging modalities, multimodal imaging techniques have been developed. An important challenge is to design all-in-one contrast agents that can be detected by multimodal techniques. Magnetoliposomes are efficient multimodal contrast agents. They can simultaneously bear both kinds of contrast and can, furthermore, incorporate targeting ligands and chains of polyethylene glycol to enhance the accumulation of nanoparticles at the site of interest and the bioavailability, respectively. Here, we review the most important characteristics of the nanoparticles or complexes used as MRI contrast agents.

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.

Selective X-ray contrast enhancement of the spleen of living mice mediated by gold nanorods.

Gold nanomaterials (AuNPs) represent a promising new class of contrast agents for X-ray computed tomographic (CT) imaging in both research and clinical settings. These materials exhibit superior X-ray absorption properties compared with other iodinated agents, and thus require lower injection doses. Gold is nonimmunogenic and therefore contributes to safety profile in living specimens. Unfortunately, most reports on the use of AuNPs as X-ray CT enhancers only demonstrate marginal enhancement of the intended anatomical structure. In this study, we demonstrate the dramatic properties of gold nanorods (GNR) to serve as robust X-ray CT contrast-enhancing agent for selective imaging of the spleen. These organ-specific uptake properties were delineated by performing longitudinal CT imaging of living mice that were dosed with GNR at 2 day intervals. Rapid uptake in spleen was noted within 12 h of first systemic administration with a change in contrast enhancement of 90 Hounsfield units (ΔHU = 90) and with two subsequent injections a total contrast enhancement of over 200 HU was observed. The resulting images provide excellent contrast that will enable the detailed anatomical visualization and study of a range of pre-clinical models of spleen disease including infection and cancer.

Semiconducting polymer nanoparticles as photoacoustic molecular imaging probes in living mice

Photoacoustic (PA) imaging holds great promise for the visualization of physiology and pathology at the molecular level with deep tissue penetration and fine spatial resolution. To fully utilize this potential, PA molecular imaging probes have to be developed. Herein we introduce near infrared (NIR) light absorbing semiconducting polymer nanoparticles (SPNs) as a new class of contrast agents for PA molecular imaging. SPNs can produce stronger signal than commonly used single-wall carbon nanotubes and gold nanorods on a per mass basis, permitting whole-body lymph node PA mapping in living mice at a low systematic injection mass. Furthermore, SPNs possess high structural flexibility, narrow PA spectral profiles, and strong resistance to photodegradation and oxidation, which enables development of the first NIR ratiometric PA probe for in vivo real-time imaging of reactive oxygen species—vital chemical mediators of many diseases. These results demonstrate SPNs an ideal nanoplatform for developing PA molecular probes.

Poly-ε-caprolactone tungsten oxide nanoparticles as a contrast agent for X-ray computed tomography

Inorganic nanomaterials based on heavy elements represent a new class of contrast agents for X-ray computed tomography (CT). Recent advances have shown that these materials are highly suited for CT imaging due to their high density and X-ray absorption capabilities. In this contribution, we demonstrated that tungsten oxide (WO3) nanoparticles coated by poly-ε-caprolactone (PCL) can be used as efficient contrast agent for CT imaging. The obtained particles were characterized by electron microscopy (TEM and SEM), and dynamic light scattering (DLS). We also validated their use for enhanced in vivo imaging, since these nanoparticles were observed to display high X-ray attenuation properties and circulation time (up to 3 h), permitting blood pool imaging.

Organometallic carbonyl clusters: a new class of contrast agents for photoacoustic cerebral vascular imaging

We report, for the first time, the use of a water-soluble organometallic compound as a stable, reliable and high-contrast photoacoustic contrast agent. This gives a significantly higher contrast than that achievable with alternatives such as single-walled carbon nanotubes. Image enhancement of the rat cerebral cortex vasculature was observed using in vivo dark-field photoacoustic microscopy.

Fibrin-Targeting, Peptide Amphiphile Micelles as Contrast Agents for Molecular MRI

Magnetic resonance imaging (MRI) provides a nonionizing and safe imaging modality for cancer diagnostics. Here, we took advantage of the fibrin deposition that is characteristic of tumors and the ability to incorporate multiple functionalities within peptide amphiphile micelles (PAMs) to design a new class of contrast agents for molecular MRI. We report on synthesis, formulation, and preliminary tests for MRI of spherical PAMs that were self-assembled by combining 18:0 PE-DTPA (Gd) and peptide amphiphiles containing the fibrin-binding pentapeptide, cysteinearginine- glutamic acid-lysine-alanine, or CREKA. Conjugation of the CREKA peptide to micelles increased the average particle size and zeta potential, and T1 relaxivities of CREKA-Gd PAMs (per mmol of Gd) were found to be comparable to contrast agents which are used routinely in clinical settings at 1.5T and 3T. Moreover, when murine fibroblasts were cultured with CREKA-Gd PAMs, no cytotoxicity was demonstrated and cell viability was comparable to that of PBS-treated controls for up to 3 days.Our study provides proof-of-concept of CREKA-Gd PAMs as contrast agents for molecular MRI, and a facile strategy for incorporating contrast agents and bioactive molecules into nano carriers to develop safe, targeted diagnostic carriers for clinical application.

Targeted drug delivery with focused ultrasound-induced blood-brain barrier opening using acoustically-activated nanodroplets

Focused ultrasound (FUS) in the presence of systemically administered microbubbles has been shown to locally, transiently and reversibly increase the permeability of the blood–brain barrier (BBB), thus allowing targeted delivery of therapeutic agents in the brain for the treatment of central nervous system diseases. Currently, microbubbles are the only agents that have been used to facilitate the FUS-induced BBB opening. However, they are constrained within the intravascular space due to their micron-size diameters, limiting the delivery effect at or near the microvessels. In the present study, acoustically-activated nanodroplets were used as a new class of contrast agents to mediate FUS-induced BBB opening in order to study the feasibility of utilizing these nanoscale phase-shift particles for targeted drug delivery in the brain. Significant dextran delivery was achieved in the mouse hippocampus using nanodroplets at clinically relevant pressures. Passive cavitation detection was used in the attempt to establish a correlation between the amount of dextran delivered in the brain and the acoustic emission recorded during sonication. Conventional microbubbles with the same lipid shell composition and perfluorobutane core as the nanodroplets were also used to compare the efficiency of an FUS-induced dextran delivery. It was found that nanodroplets had a higher BBB opening pressure threshold but a lower stable cavitation threshold than microbubbles, suggesting that contrast agent-dependent acoustic emission monitoring was needed. A more homogeneous dextran delivery within the targeted hippocampus was achieved using nanodroplets without inducing inertial cavitation or compromising safety. Our results offered a new means of developing the FUS-induced BBB opening technology for potential extravascular targeted drug delivery in the brain, extending the potential drug delivery region beyond the cerebral vasculature.