X-ray Computed Tomography Contrast Agents Research Articles

Heavy Metal-Based Nanoparticles as High-Performance X-ray Computed Tomography Contrast Agents.

X-ray computed tomography (CT) contrast agents offer extremely valuable tools and techniques in diagnostics via contrast enhancements. Heavy metal-based nanoparticles (NPs) can provide high contrast in CT images due to the high density of heavy metal atoms with high X-ray attenuation coefficients that exceed that of iodine (I), which is currently used in hydrophilic organic CT contrast agents. Nontoxicity and colloidal stability are vital characteristics in designing heavy metal-based NPs as CT contrast agents. In addition, a small particle size is desirable for in vivo renal excretion. In vitro phantom imaging studies have been performed to obtain X-ray attenuation efficiency, which is a critical parameter for CT contrast agents, and the imaging performance of CT contrast agents has been demonstrated via in vivo experiments. In this review, we focus on the in vitro and in vivo studies of various heavy metal-based NPs in pure metallic or chemical forms, including Au, Pt, Pd, Ag, Ce, Gd, Dy, Ho, Yb, Ta, W, and Bi, and provide an outlook on their use as high-performance CT contrast agents.

Development of self-powered multifunctional piezomagnetic nanoparticles for non-invasive post-surgical osteosarcoma theranogeneration

Non-invasive treatment approaches are gaining increased attention in recent times due to the potential improvement in treatment efficiency. Here we report a brand-new ultrasound (US), magnetic field (MF), and light responsive nanoparticle system based on piezoelectric barium titanate and superparamagnetic iron oxide nanoparticles termed as PiezoMagnetic nanoparticles (PMNPs) for the multimodal anticancer treatment, complimentary imaging, and non-invasive cell stimulation. Systematic electrical studies reveal that PMNPs exhibit superior ferroelectric and conducting properties and produce electrical signals analogous to native tissues when mechanically stimulated and using Food and Drug Administration (FDA) approved Low intensity Pulsed Ultrasound (LIPUS) non-invasively for cell stimulation. The green energy generation from PMNPs are further proved by the real-time demonstration of commercial LED lit-up. Thus, as a proof of concept, we have demonstrated a stepwise treatment efficacy of PMNPs for the post-surgical osteosarcoma therapy, diagnosis, and regeneration (termed as Theranogeneration). The PMNPs exhibited excellent anticancer properties to eradicate the residual osteosarcoma cells by magnetic hyperthermia, photothermal and photodynamic therapy along with complimentary imaging capabilities as X-ray computed tomography contrast agent and label free fluorescent probe. The conjugation of risedronate R (RIS)- a new generation bisphosphonates to PMNPs imparted bone seeking property to PMNPs. Therefore, as a result of noninvasive cell stimulation properties of PMNPs under LIPUS and LIPUS mediated RIS release from PMNPs resulted in enhanced bone regeneration and bone turnover which helps to repair the large bone defects occurs in osteosarcoma resection. Thus, the study corroborates the development of a potential bioactive piezoelectric nanoplatform that can be used to control the cell behaviour and fate in order to develop new types of therapies for multiple diseases including various types of cancers in remotely controlled approaches.

In situ x-ray-induced acoustic computed tomography with a contrast agent: a proof of concept.

X-ray-induced acoustic computed tomography (XACT) has shown great potential as a hybrid imaging modality for real-time non-invasive x-ray dosimetry and low-dose three-dimensional (3D) imaging. While promising, one drawback of the XACT system is the underlying low signal-to-noise ratio (SNR), limiting its in vivo clinical use. In this Letter, we propose the first use of a conventional x-ray computed tomography contrast agent, Gastrografin, for improving the SNR of in situ XACT imaging. We obtained 3D volumetric XACT images of a mouse's stomach with orally injected Gastrografin establishing the proposal's feasibility. Thus, we believe, in the future, our proposed technique will allow in vivo imaging and expand or complement conventional x-ray modalities, such as radiotherapy and accelerators.

Functionalized Lanthanide Oxide Nanoparticles for Tumor Targeting, Medical Imaging, and Therapy.

Recent progress in functionalized lanthanide oxide (Ln2O3) nanoparticles for tumor targeting, medical imaging, and therapy is reviewed. Among the medical imaging techniques, magnetic resonance imaging (MRI) is an important noninvasive imaging tool for tumor diagnosis due to its high spatial resolution and excellent imaging contrast, especially when contrast agents are used. However, commercially available low-molecular-weight MRI contrast agents exhibit several shortcomings, such as nonspecificity for the tissue of interest and rapid excretion in vivo. Recently, nanoparticle-based MRI contrast agents have become a hot research topic in biomedical imaging due to their high performance, easy surface functionalization, and low toxicity. Among them, functionalized Ln2O3 nanoparticles are applicable as MRI contrast agents for tumor-targeting and nontumor-targeting imaging and image-guided tumor therapy. Primarily, Gd2O3 nanoparticles have been intensively investigated as tumor-targeting T1 MRI contrast agents. T2 MRI is also possible due to the appreciable paramagnetic moments of Ln2O3 nanoparticles (Ln = Dy, Ho, and Tb) at room temperature arising from the nonzero orbital motion of 4f electrons. In addition, Ln2O3 nanoparticles are eligible as X-ray computed tomography contrast agents because of their high X-ray attenuation power. Since nanoparticle toxicity is of great concern, recent toxicity studies on Ln2O3 nanoparticles are also discussed.

Metallic nanoparticles as X-Ray computed tomography (CT) contrast agents: A review

X-ray computed tomography vastly used in both medical purposes and in the research of biological and non-biological materials/samples. Some of the medical applications performed in the clinics requires special protocols where contrast agents may be needed to enhance the contrast. Iodine based contrast agents are commonly used in such applications. Iodine based contrast agents were found hazardous to the environment and some patients has iodine in tolerance due to thyroid origin diseases. Scientists from different fields try to develop contrast agents which can be an alternative to iodine based contrast agents. Metallic nanoparticles have potential to be used as CT contrast agent since metals has high X-ray attenuation and high density. Metal nanoparticles considered as toxic to the living organisms. Covering nanoparticles with organic molecule often reduce toxicity and enhance the biocompatibility. Decoration of nanoparticles with function groups give them targeting properties where special organ and/or tissue can be targeted. Up to now, different studies illustrated the importance of the multipurpose properties of the metallic nanoparticles. In this report, we assessed the metal nanoparticles reported as X-ray computed tomography contrast agent. For the first time in the literature we listed in vivo contrast enhancement, targeted drug delivery and dual/multipurpose imaging properties of each metallic nanoparticles. Therapeutic effects of metallic nanoparticles such as photothermal therapy and magnetic hyperthermia were also addressed. A chart showing relative contrast enhancement properties of the nanoparticles were produced.

Bimodal Nd-Doped LuVO4 Nanoprobes Functionalized with Polyacrilic Acid for X-Ray Computed Tomography and NIR Luminescent Imaging.

Uniform Nd3+-doped LuVO4 nanophosphors have been synthesized for the first time in literature by using a poliol-based method at 120 °C from Nd3+ and vanadate precursors. After optimizing the Nd doping level, these phosphors present intense luminescence in the near-infrared biological windows. The X-ray attenuation capacity of the optimum nanophosphor has been found to be higher than that of a commercial X-ray computed tomography contrast agent. After surface coating with polyacrylic acid, such nanoparticles present high colloidal stability in physiological pH medium and high cell viability. Because of these properties, the developed Nd3+-doped LuVO4 nanoparticles have potential applications as a bimodal probe for NIR luminescent bioimaging and X-ray computed tomography.

Synthesis, functionalization and properties of uniform europium-doped sodium lanthanum tungstate and molybdate (NaLa(XO4)2, X = Mo,W) probes for luminescent and X-ray computed tomography bioimaging

A one-pot simple procedure for the synthesis of uniform, ellipsoidal Eu3+-doped sodium lanthanum tungstate and molybdate (NaLa(XO4)2, X = W, Mo) nanophosphors, functionalized with carboxylate groups, is described. The method is based on a homogeneous precipitation process at 120 °C from appropriate Na+, Ln3+ and tungstate or molybdate precursors dissolved in ethylene glycol/water mixtures containing polyacrylic acid. A comparative study of the luminescent properties of both luminescent materials as a function of the Eu3+ doping level has been performed to find the optimum nanophosphor, whose efficiency as X-ray computed tomography contrast agent is also evaluated and compared with that of a commercial probe. Finally, the cell viability and colloidal stability in physiological pH medium of the optimum samples have also been studied to assess their suitability for biomedical applications.

Room temperature synthesis of water-dispersible Ln3+:CeF3 (Ln = Nd, Tb) nanoparticles with different morphology as bimodal probes for fluorescence and CT imaging

The singular properties of lanthanide-based inorganic nanoparticles (NPs) has raised the attention of the scientific community in biotechnological applications. In particular, those systems with two or more functionalities are especially interesting. In this work, an effective and commercially attractive procedure has been developed that renders uniform, water-dispersible Ln3+:CeF3 (Ln = Tb, Nd) NPs with different shapes and size. The method consists of the homogeneous precipitation, in a mixture of polyol and water, of cations and anions using precursors that allow the controlled release of the latter. The advantages of the reported method are related to the absence of surfactants, dispersing agents or corrosive precursors as well as to the room temperature of the process. The obtained Tb:CeF3 NPs produce an intense emission after excitation through the Ce-Tb energy transfer band located in the UV spectral region, thus being potentially useful as phosphors for in-vitro imaging purposes. On the other hand, the synthesized Nd:CeF3 NPs are good candidates for in-vivo imaging because their excitation and emission wavelengths lie in the biological windows. Finally, the excellent X-ray attenuation efficacy of the Nd:CeF3 NPs is shown, which confers double functionality to this material as both luminescence bioprobe and contrast agent for X-ray computed-tomography.

Highly water-stable rare ternary Ag-Au-Se nanocomposites as long blood circulation time X-ray computed tomography contrast agents.

X-ray computed tomography (CT) is a powerful and widely used medical non-invasive technique that often requires intravenous administration of contrast agents (CAs) to better visualize soft tissues. In this work, we have developed a novel CT contrast agent based on ternary Ag-Au-Se chalcogenide nanoparticles (NP). A facile ligand exchange by using a 3 kDa PEGylated ligand with a dithiol dihydrolipoic acid as an anchor group resulted in highly water-soluble and monodisperse nanoparticles. These PEGylated ternary NPs were tested in vivo in mice, showing slow uptake by the mononuclear phagocyte system, long blood circulation times, low toxicity, and very good X-ray contrast, thus being promising candidates as CT contrast agents for clinical applications.

Nontoxic Formulations of Scintillation Nanocrystals for Use as X-ray Computed Tomography Contrast Agents

X-ray computed tomography (CT) is currently one of the most powerful, noninvasive, clinical in vivo imaging techniques, which has resulted from advances in both X-ray device and contrast enhancement technologies. The present study demonstrates, for the first time, that metal tungstates (such as CaWO4) are promising contrast agents for X-ray, radiation, and CT imaging, because of the high X-ray mass attenuation of tungsten (W). We have developed a method of formulation, in which CaWO4 (CWO) nanoparticles (NPs) are encapsulated within a biocompatible poly(ethylene glycol-b-d,l-lactic acid) (PEG-PLA) block copolymer (BCP) capsule. We show that these PEG-PLA-encapsulated CWO NPs (170 ± 10 nm hydrodynamic diameter) produce a higher CT contrast (by a factor of about 2) than commercial iodine-based radiocontrast agents (e.g., Iohexol) at identical molar concentrations of W or I atoms. PEG-PLA-coated CWO NPs are chemically stable and completely nontoxic. It was confirmed that the maximum tolerated dose (MTD) of this material in mice is significantly higher (250 ± 50 mg per kg body weight following a single intravenous (IV) administration) than, for instance, commercially available dextran-coated iron oxide nanoparticles that are currently used clinically as MRI contrast agents (MTD in mice ≈ 168 mg/kg per dose IV). IV-injected PEG-PLA/CWO NPs caused no histopathologic damage in major excretory organs (heart, liver, lungs, spleen, and kidney). When an IV dose of 100 mg/kg was given to mice, the blood circulation half-life was measured to be about 4 h, and more than 90% of the NPs were cleared from the mice within 24 h via the renal and hepatobiliary systems. When intratumorally administered, PEG-PLA-coated CWO NPs showed complete retention in a tumor-bearing mouse model (measurements were made up to 1 week). These results suggest that PEG-PLA-coated CWO NPs are promising materials for use in CT contrast.

Nanoparticulate X-ray Computed Tomography Contrast Agents: From Design Validation to in Vivo Applications

X-ray computed tomography (CT) is one of the most powerful noninvasive diagnostic imaging techniques in modern medicine. Nevertheless, the iodinated molecules used as CT contrast agents in the clinic have relatively short circulation times in vivo, which significantly restrict the applications of this technique in target-specific imaging and angiography. In addition, the use of these agents can present adverse. For example, an adult patient typically receives approximately 70 mL of iodinated agent (350 mg I/mL) because of iodine's low contrast efficacy. Rapid renal clearance of such a large dose of these agents may lead to serious adverse effects. Furthermore, some patients are hypersensitive to iodine. Therefore, biomedical researchers have invested tremendous efforts to address these issues. Over the past decade, advances in nanoscience have created new paradigms for imaging. The unique properties of nanomaterials, such as their prolonged circulating half-life, passive accumulation at the tumor sites, facile surface modification, and integration of multiple diverse functions into a single particle, make them advantageous for in vivo applications. However, research on the utilization of nanomaterials for CT imaging has lagged far behind their applications for other imaging techniques such as MRI and fluorescence imaging because of the challenges in the preparation of cost-effective nanoparticulate CT contrast agents with excellent biocompatibility, high contrast efficacy, long in vivo circulation time, and long-term colloidal stability in physiological environments. This Account reviews our recent work on the design and in vivo applications of nanoparticulate CT contrast agents. By optimizing the contrast elements in the nanoparticles according to the fundamental principles of X-ray imaging and by employing the surface engineering approaches that we and others have developed, we have synthesized several nanoparticulate CT contrast agents with excellent imaging performance. For example, a novel Yb-based nanoparticulate agent provides enhanced contrast efficacy compared to currently available CT contrast agents under normal operating conditions. To deal with special situations, we integrated both Ba and Yb with great differential in K-edge value into a single particle to yield the first example of binary contrast agents. This agent displays much higher contrast than iodinated agents at different voltages and is highly suited to diagnostic imaging of various patients. Because of their prolonged in vivo circulation time and extremely low toxicity, these agents can be used for angiography.

X-ray computed tomography contrast agents prepared by seeded growth of goldnanoparticles in PEGylated dendrimer

Gold nanoparticles (Au NPs) are a potential x-ray computed tomography (CT) contrastagent. A biocompatible and bioinactive surface is necessary for application of goldnanoparticle to CT imaging. Polyethylene glycol (PEG)-attached dendrimers have beenused as a drug carrier with long blood circulation. In this study, the Au NPs weregrown in the PEGylated dendrimer to produce a CT contrast agent. The AuNPs were grown by adding gold ions and ascorbic acid at various equivalentsto the Au NP-encapsulated dendrimer solution. Both size and surface plasmonabsorption of the grown Au NPs increased with adding a large number of gold ions.The x-ray attenuation of the Au NPs also increased after the seeded growth.The Au NPs grown in the PEG-attached dendrimer at the maximum under ourconditions exhibited a similar CT value to a commercial iodine agent, iopamidol,in vitro. The Au NP-loaded PEGylated dendrimer and iopamidol were injectedinto mice and CT images were obtained at different times. The Au NP-loadedPEGylated dendrimer achieved a blood pool imaging, which was greater thana commercial iodine agent. Even though iopamidol was excreted rapidly, thePEGylated dendrimer loading the grown Au NP was accumulated in the liver.

AuNP-DG: Deoxyglucose-Labeled Gold Nanoparticles as X-ray Computed Tomography Contrast Agents for Cancer Imaging

To study the feasibility of using 2-deoxy-D-glucose (2-DG)-labeled gold nanoparticle (AuNP-DG) as a computed tomography (CT) contrast agent with tumor targeting capability through in vitro experiments. Gold nanoparticles (AuNP) were fabricated and were conjugated with 2-deoxy-D-glucose. The human alveolar epithelial cancer cell line, A-549, was chosen for the in vitro cellular uptake assay. Two groups of cell samples were incubated with the AuNP-DG and the unlabeled AuNP, respectively. Following the incubation, the cells were washed with sterile PBS to remove the excess gold nanoparticles and spun to cell pellets using a centrifuge. The cell pellets were imaged using a microCT scanner immediately after the centrifugation. The reconstructed CT images were analyzed using a commercial software package. Significant contrast enhancement in the cell samples incubated with the AuNP-DG with respect to the cell samples incubated with the unlabeled AuNP was observed in multiple CT slices. Results from this study demonstrate enhanced uptake of 2-DG-labeled gold nanoparticle by cancer cells in vitro and warrant further experiments to study the exact molecular mechanism by which the AuNP-DG is internalized and retained in the tumor cells.

WE-D-303A-02: Deoxyglucose Labeled Gold Nanoparticles as X-Ray Computed Tomography Contrast Agents for Cancer Imaging

Purpose: To study the feasibility of using 2‐Deoxy‐D‐Glucose (2‐DG) labeled gold nanoparticle (AuNP‐DG) as a metabolic functional CTcontrast agent through in vitro experiments. Method and Materials: The goldnanoparticles (AuNP) were fabricated using a citrate acid reduction method. The size of the AuNP was determined from Transmission Electron Microscopy images to be 4 nm in diameter. The conjugation of the 2‐DG with the AuNP core was accomplished using mercapto group in the 2‐carbon position by condensation reaction of 2‐amino‐deoxyglucose with mercaptosuccinic acid. The human alveolar epithelial cancer cell line, A‐549, was chosen for the in vitro cellular uptake assay. Two groups of cell samples (∼1 × 105 cells per sample) were incubated with the AuNP‐DG and the unlabeled AuNP, respectively, for 30 minutes (37°C, 7% CO2). Following the incubation, the cells were washed with sterile PBS six times to remove the excess goldnanoparticles. The cells were then spun to cell pellets using a centrifuge. The cell pellets were imaged using a microCT scanner immediately after the centrifuging (75 kVp, 135 μA, 1184 × 1120 matrix size, 360 views, averaging 5 frames per view). The reconstructedCTimages were analyzed using a commercial software package. Results: Significant contrast enhancement in the cell samples incubated with the AuNP‐DG with respect to the cell samples incubated with the unlabeled AuNP was observed in multiple CT slices. Quantitative analysis of the image data showed that (45.6 ± 14.2)% of the cells that were incubated with the AuNP‐DG exhibit enhanced contrast compared to the cells in the control group (incubated with AuNP). Conclusion: Results from these experiments strongly suggest enhanced uptake of the AuNP‐DG over the unlabeled AuNP by the highly glycolytic cancer cells in vitro and indicate that AuNP‐DG could served as a metabolic functional CTcontrast agent with tumor‐specific targeting capability.