Nanoparticle-based Contrast Agents Research Articles

Tracking mesenchymal stem cell tumor-homing using fluorescent silica nanoparticles.

Stem cell tracking can reveal the underlying biological processes of stem-cell-based therapies such as the migration and biodistribution of human mesenchymal stem cells (hMSCs) in cancer therapy. Nanoparticle-based contrast agents offer unprecedented opportunities for achieving this goal due to their unique and tunable imaging capabilities. However, most nanoparticles are still in the process of development due to challenges such as retention time and safety issues, and are inaccessible to most researchers. In this article, we investigate the potential application of core-shell fluorescent silica nanoparticles (i.e. C dots), which are commercially available and approved by the FDA for clinical trials. Specifically we demonstrate that 500 nm C dots have prolonged cellular retention (up to one month), minimal contrast agent transfer (at least three weeks) between cells in a co-culture Boyden chamber system, and minimal influence on the hMSC properties including viability, proliferation, differentiation, and tropism to tumor cells.

Time Course of Contrast Enhancement by Micro-CT with Dedicated Contrast Agents in Normal Mice and Mice with Hepatocellular Carcinoma: Comparison of One Iodinated and Two Nanoparticle-Based Agents

The aim of the present study was to characterize the kinetics of two nanoparticle-based contrast agents for preclinical imaging, Exitron nano 6000 and Exitron nano 12000, and the iodinated agent eXIA 160 in both healthy mice and in a mouse model of hepatocellular carcinoma (HCC). Semiautomatic segmentation of liver lesions for estimation of total tumor load of the liver was evaluated in HCC mice. The normal time course of contrast enhancement was assessed in 15 healthy C57BL/6 mice. Imaging of tumor spread in the liver was evaluated in 15 mice harboring a transgenic HCC model (ASV-B mice). Automatic segmentation of liver lesions for determination of total tumor burden of the liver was tested in three additional ASV-B mice before and after an experimental therapy. In healthy mice, clearance of the contrast agent from blood was completed within 3-4hours for eXIA 160 and Exitron nano 6000, whereas complete blood clearance of Exitron nano 12000 required about 24hours. eXIA 160 provided maximum liver contrast at 1hour post injection (p.i.) followed by a continuous decline. Enhancement of liver contrast with Exitron nano 6000 and Exitron nano 12000 reached a plateau at about 4hours p.i., which lasted until the end of the measurements at 96hours p.i. Maximum contrast enhancement of the liver was not statistically different between Exitron nano 6000 and Exitron nano 12000, but was about three times lower for eXIA 160 (P<.05). Visually Exitron nano 12000 provided the best liver-to-tumor contrast. Semiautomatic liver and tumor segmentation was feasible after the administration of Exitron nano 12000 but did not work properly for the other two contrast agents. Both nanoparticle-based contrast agents provided stronger and longer lasting contrast enhancement of healthy liver parenchyma. Exitron nano 12000 allowed automatic segmentation of tumor lesions for estimation of the total tumor load in the liver.

Assessing Cardiac Injury in Mice With Dual Energy-MicroCT, 4D-MicroCT, and MicroSPECT Imaging After Partial Heart Irradiation

To develop a mouse model of cardiac injury after partial heart irradiation (PHI) and to test whether dual energy (DE)-microCT and 4-dimensional (4D)-microCT can be used to assess cardiac injury after PHI to complement myocardial perfusion imaging using micro-single photon emission computed tomography (SPECT). To study cardiac injury from tangent field irradiation in mice, we used a small-field biological irradiator to deliver a single dose of 12 Gy x-rays to approximately one-third of the left ventricle (LV) of Tie2Cre; p53(FL/+) and Tie2Cre; p53(FL/-) mice, where 1 or both alleles of p53 are deleted in endothelial cells. Four and 8 weeks after irradiation, mice were injected with gold and iodinated nanoparticle-based contrast agents, and imaged with DE-microCT and 4D-microCT to evaluate myocardial vascular permeability and cardiac function, respectively. Additionally, the same mice were imaged with microSPECT to assess myocardial perfusion. After PHI with tangent fields, DE-microCT scans showed a time-dependent increase in accumulation of gold nanoparticles (AuNp) in the myocardium of Tie2Cre; p53(FL/-) mice. In Tie2Cre; p53(FL/-) mice, extravasation of AuNp was observed within the irradiated LV, whereas in the myocardium of Tie2Cre; p53(FL/+) mice, AuNp were restricted to blood vessels. In addition, data from DE-microCT and microSPECT showed a linear correlation (R(2) = 0.97) between the fraction of the LV that accumulated AuNp and the fraction of LV with a perfusion defect. Furthermore, 4D-microCT scans demonstrated that PHI caused a markedly decreased ejection fraction, and higher end-diastolic and end-systolic volumes, to develop in Tie2Cre; p53(FL/-) mice, which were associated with compensatory cardiac hypertrophy of the heart that was not irradiated. Our results show that DE-microCT and 4D-microCT with nanoparticle-based contrast agents are novel imaging approaches complementary to microSPECT for noninvasive assessment of the change in myocardial vascular permeability and cardiac function of mice in whom myocardial injury develops after PHI.

Lectin-Conjugated Fe2O3@Au Core@Shell Nanoparticles as Dual Mode Contrast Agents for in Vivo Detection of Tumor

Here, we report the covalent conjugation of lectin on Fe2O3@Au core@shell nanoparticle (lectin-Fe2O3@Au NP) for T2-weighted magnetic resonance (MR) and X-ray computed tomography (CT) dual-modality imaging. The lectin-Fe2O3@Au NPs are prepared by coupling lectins to the Fe2O3@Au NP surfaces through bifunctional PEG NHS ester disulfide (NHS-PEG-S-S-PEG-NHS) linkers. After the nonspecific adsorption sites on the nanoparticle surface are blocked by thiolated PEG (PEG-SH), the lectin-Fe2O3@Au NPs exhibit excellent stability in biological medium and inappreciable cytotoxicity. A series of in vitro and in vivo experiments were then carried out for evaluating the capabilities of three selected lectin (ConA, RCA and WGA)-Fe2O3@Au NPs. The results revealed that the lectin-Fe2O3@Au NPs had a capacity not only for dual mode MR and CT imaging in vitro but also for MR and CT imaging of colorectal cancer in vivo. The experimental results also suggest that lectin could be used as tumor targeting ligand for synthesizing nanoparticle-based contrast agents.

Biodegradable human serum albumin nanoparticles as contrast agents for the detection of hepatocellular carcinoma by magnetic resonance imaging

Tumor visualization by magnetic resonance imaging (MRI) and nanoparticle-based contrast agents may improve the imaging of solid tumors such as hepatocellular carcinoma (HCC). In particular, human serum albumin (HSA) nanoparticles appear to be a suitable carrier due to their safety and feasibility of functionalization. In the present study HSA nanoparticles were conjugated with gadolinium diethylenetriaminepentaacetic acid (Gd-DTPA) using carbodiimide chemistry. The nanoparticles had a uniform spherical shape and a diameter of 235±19nm. For better optical visualization in vitro and in vivo, the HSA-Gd nanoparticles were additionally labeled with rhodamine 123. As shown by confocal microscopy and flow cytometry analysis, the fluorescent nanoparticles were readily taken up by Huh-7 hepatocellular carcinoma cells. After 24h incubation in blood serum, less than 5% of the Gd(III) was released from the particles, which suggests that this nanoparticulate system may be stable in vivo and, therefore, may serve as potentially safe T1 MRI contrast agent for MRI of hepatocellular carcinoma.

Nanoparticle-based systems for T(1)-weighted magnetic resonance imaging contrast agents.

Because magnetic resonance imaging (MRI) contrast agents play a vital role in diagnosing diseases, demand for new MRI contrast agents, with an enhanced sensitivity and advanced functionalities, is very high. During the past decade, various inorganic nanoparticles have been used as MRI contrast agents due to their unique properties, such as large surface area, easy surface functionalization, excellent contrasting effect, and other size-dependent properties. This review provides an overview of recent progress in the development of nanoparticle-based T1-weighted MRI contrast agents. The chemical synthesis of the nanoparticle-based contrast agents and their potential applications were discussed and summarized. In addition, the recent development in nanoparticle-based multimodal contrast agents including T1-weighted MRI/computed X-ray tomography (CT) and T1-weighted MRI/optical were also described, since nanoparticles may curtail the shortcomings of single mode contrast agents in diagnostic and clinical settings by synergistically incorporating functionality.

Functionalized nanomaterials: their use as contrast agents in bioimaging: mono- and multimodal approaches

AbstractThe successful development of nanomaterials illustrates the considerable interest in the development of new molecular probes for medical diagnosis and imaging. Substantial progress was made in the synthesis protocol and characterization of these materials, whereas toxicological issues are sometimes incomplete. Nanoparticle-based contrast agents (CAs) tend to become efficient tools for enhancing medical diagnostics and surgery for a wide range of imaging modalities. The multimodal nanoparticles (NPs) are much more efficient than the conventional molecular-scale CAs. They provide new abilities for in vivo detection and enhanced targeting efficiencies through longer circulation times, designed clearance pathways, and multiple binding capacities. Properly protected, they can safely be used for the fabrication of various functional systems with targeting properties, reduced toxicity, and proper removal from the body. This review mainly describes the advances in the development of mono- to multimodal NPs and their in vitro and in vivo relevant biomedical applications ranging from imaging and tracking to cancer treatment. Besides the specific applications for classical imaging (magnetic resonance imaging, positron emission tomography, computed tomography, ultrasound, and photoacoustic imaging), the less common imaging techniques such as terahertz molecular imaging (THMI) or ion beam analysis (IBA) are mentioned. The perspectives on the multimodal theranostic NPs and their potential for clinical advances are also mentioned.

Nanoparticle-based Monitoring of Stem Cell Therapy

This theme issue provides a timely overview on the current status of stem cell tracking with the nanoparticle-based contrast agents.

In situ growth of β-FeOOH nanorods on graphene oxide with ultra-high relaxivity for in vivo magnetic resonance imaging and cancer therapy.

β-FeOOH has shown promise as a new contrast agent in magnetic resonance imaging (MRI), however, sensitive and accurate MR imaging is largely limited by its low transverse relaxivity (r2). Herein, for the first time we report in situ growth of β-FeOOH nanorods onto PEGylated graphene oxide (GO) sheets to produce a nanocomposite, e.g., GO-PEG-β-FeOOH. This nanocomposite exhibits a record ultra-high transverse relaxivity (r2) value of 303.81 mM-1 s-1, that is, >60 times higher than those achieved by hitherto reported β-FeOOH based MRI contrast agents. This well facilitates its practical use as a contrast agent for in vivo MR imaging. PEG on the surface of the GO nanocomposite improved the colloidal stability in aqueous medium. In addition, in vitro cell viability tests demonstrated that GO-PEG-β-FeOOH has minimal cellular toxicity. GO-PEG-β-FeOOH has been used for loading doxorubicin hydrochloride (DOX) with a capacity of 1.35 mg mg-1, which exhibits high efficiency in Hela cell apoptosis. These results indicated that GO-PEG-β-FeOOH provides an effective alternative to the existing nanoparticle-based contrast agents for non-invasive in vivo MR imaging and cancer therapy.

Effect of Coating Materials on Lymph Nodes Detection Using Magnetite Nanoparticles

Magnetite nanoparticles-based contrast agents used in magnetic resonance imaging has offered new promise for early detection of lymph nodes and their metastases. Beside the value of Magnetite core of superparamagnetic nanoparticles as an efficient contrast agent, the type of coating material is important for their biodistribution properties. In this study, various coating materials were synthesized and their detection sensitivities were evaluated in axillary lymph nodes. These nanoparticles were prepared in an aqueous-phase under ultrasonic irradiation. Four different types of coatings including polyethylene glycol, Dextran, Carboxymethyl Dextran, and double layer of PEG-Dextran were used as the capping agents. The crystal structure, morphology, hydrodynamic size and magnetic properties of the nanoparticles were characterized. In-vitro relaxivity measurements along with post contrast in-vivo studies on rat demonstrated that the synthesized nanoparticles are applicable as magnetic resonance imaging contrast agents for imaging of the lymph nodes. In-vitro magnetic resonance imaging showed the optimum r2/r1 for Dextran nanoparticles. The best contrast to noise ratio (CNR) for in-vivo studies was obtained by the Dextran-coated nanoparticles.

Multifunctional metal ferrite nanoparticles for MR imaging applications

Magnetic Resonance Imaging (MRI) is a very powerful non-invasive tool for in vivo imaging and clinical diagnosis. With rapid advancement in nanoscience and nanotechnology, there is rapid growth in nanoparticles-based contrast agents. Progress in synthetic protocols enable synthesis of multifunctional nanoparticles which facilitated efforts toward the development of multimodal contrast agents. In this review, recent developments in metal ferrite-based MR contrast agents have been described. Specifically, effect of size, shape, composition, assembly and surface modification of metal ferrite nanoparticles on their T 2 contrast have been discussed. The review further outlines the effect of leaching on MRI contrast and other various factors which affect the multimodal ability of the (T 1–T 2 and T 2-thermal activation) metal ferrite nanoparticles.

Characterization of nanoparticle-based contrast agents for molecular magnetic resonance imaging

The development of molecular imaging agents is currently undergoing a dramatic expansion. As of October 2011, ~4,800 newly developed agents have been synthesized and characterized in vitro and in animal models of human disease. Despite this rapid progress, the transfer of these agents to clinical practice is rather slow. To address this issue, the National Institutes of Health launched the Molecular Imaging and Contrast Agents Database (MICAD) in 2005 to provide freely accessible online information regarding molecular imaging probes and contrast agents for the imaging community. While compiling information regarding imaging agents published in peer-reviewed journals, the MICAD editors have observed that some important information regarding the characterization of a contrast agent is not consistently reported. This makes it difficult for investigators to evaluate and meta-analyze data generated from different studies of imaging agents, especially for the agents based on nanoparticles. This article is intended to serve as a guideline for new investigators for the characterization of preclinical studies performed with nanoparticle-based MRI contrast agents. The common characterization parameters are summarized into seven categories: contrast agent designation, physicochemical properties, magnetic properties, in vitro studies, animal studies, MRI studies, and toxicity. Although no single set of parameters is suitable to define the properties of the various types of contrast agents, it is essential to ensure that these agents meet certain quality control parameters at the preclinical stage, so that they can be used without delay for clinical studies.

Contrast Enhancement of the Brain by Folate-Conjugated Gadolinium–Diethylenetriaminepentaacetic Acid–Human Serum Albumin Nanoparticles by Magnetic Resonance Imaging

Different from regular small molecule contrast agents, nanoparticle-based contrast agents have a longer circulation time and can be modified with ligands to confer tissue-specific contrasting properties. We evaluated the tissue distribution of polymeric nanoparticles (NPs) prepared from human serum albumin (HSA), loaded with gadolinium-diethylenetriaminepentaacetic acid (Gd-DTPA) (Gd-HSA-NP), and coated with folic acid (FA) (Gd-HSA-NP-FA) in mice by magnetic resonance imaging (MRI). FA increases the affinity of the Gd-HSA-NP to FA receptor-expressing cells. Clinical 3 T MRI was used to evaluate the signal intensities in the different organs of mice injected with Gd-DTPA, Gd-HSA-NP, or Gd-HSA-NP-FA. Signal intensities were measured and standardized by calculating the signal to noise ratios. In general, the NP-based contrast agents provided stronger contrasting than Gd-DTPA. Gd-HSA-NP-FA provided a significant contrast enhancement (CE) in the brain (p = .0032), whereas Gd-DTPA or Gd-HSA-NP did not. All studied MRI contrast agents showed significant CE in the blood, kidney, and liver (p < .05). Gd-HSA-NP-FA elicited significantly higher CE in the blood than Gd-HSA-NP (p = .0069); Gd-HSA-NP and Gd-HSA-NP-FA did not show CE in skeletal muscle and gallbladder; Gd-HSA-NP, but not Gd-HSA-NP-FA, showed CE in the cardiac muscle. Gd-HSA-NP-FA has potential as an MRI contrast agent in the brain.

ChemInform Abstract: Silica‐Based Nanoprobes for Biomedical Imaging and Theranostic Applications

AbstractReview: 60 refs.

The Effect of Nanoparticle Size on Cellular Binding Probability

Nanoparticle-based contrast agents are expected to play a major role in the future of molecular imaging due to their many advantages over the conventional contrast agents. These advantages include prolonged blood circulation time, controlled biological clearance pathways, and specific molecular targeting capabilities. Recent studies have provided strong evidence that molecularly targeted nanoparticles can home selectively onto tumors and thereby increase the local accumulation of nanoparticles in tumor sites. However, there are almost no reports regarding the number of nanoparticles that bind per cell, which is a key factor that determines the diagnostic efficiency and sensitivity of the overall molecular imaging techniques. Hence, in this research we have quantitatively investigated the effect of the size of the nanoparticle on its binding probability and on the total amount of material that can selectively target tumors, at a single cell level. We found that 90 nm GNPs is the optimal size for cell targeting in terms of maximal Au mass and surface area per single cancer cell. This finding should accelerate the development of general design principles for the optimal nanoparticle to be used as a targeted imaging contrast agent.

Inorganic Nanoparticles Based Contrast Agents for X‐ray Computed Tomography

Nanomaterials have gained considerable attention and interest in the development of new and efficient molecular probes for medical diagnosis and imaging. Heavy metal nanoparticles as such are excellent absorber of X-rays and can offer excellent improvement in medical diagnosis and X-ray imaging. Substantial progress has been made in the synthesis protocol and characterization studies of these materials but a major challenge still lies in the toxicological studies, which are rather incomplete. The worst known cases were those associated with Thorotrast (suspension of ThO(2) nanoparticles) which resulted in many deaths over years. Properly protected nanomaterials conjugated or coated with biocompatible materials can be used for the fabrication of various functional systems with multimodality, targeting properties, reduced toxicity and proper removal from the body. This review aims mainly to provide the advances in the development of inorganic nanoparticle based X-ray contrasting agents with an overview of methods of their preparation, functionalization and applications in medical diagnosis.

Radioluminescent nanophosphors enable multiplexed small-animal imaging

We demonstrate the ability to image multiple nanoparticle-based contrast agents simultaneously using a nanophosphor platform excited by either radiopharmaceutical or X-ray irradiation. These radioluminescent nanoparticles emit optical light at unique wavelengths depending on their lanthanide dopant, enabling multiplexed imaging. This study demonstrates the separation of two distinct nanophosphor contrast agents in gelatin phantoms with a recovered phosphor separation correlation of −0.98. The ability to distinguish the two nanophosphors and a Cerenkov component is then demonstrated in a small animal phantom. Combined with the high-resolution potential of low-scattering X-ray excitation, this imaging technique may be a promising method to probe molecular processes in living organisms.

Silica-based nanoprobes for biomedical imaging and theranostic applications

Nanoparticle-based contrast agents are attracting a great deal of attention for various biomedical imaging and theranostic applications. Compared to conventional contrast agents, nanoparticles possess several potential advantages to improve in vivo detection and to enhance targeting efficiency. Silica-based nanoprobes can be engineered to achieve longer blood circulation times, specific clearance pathways, and multivalent binding. In this tutorial review, we summarize the latest progress on designing silica-based nanoprobes for imaging and theranostic applications. The synthesis of both solid silica and mesoporous silica nanoparticles is described, along with different approaches used for surface functionalization. Special emphasis is placed on the application of silica-based nanoprobes in optical, magnetic resonance, and multimodal imaging. The latest breakthroughs in the applications of silica nanoparticles as theranostic agents are also highlighted.

Specific labelling of cell populations in blood with targeted immuno-fluorescent/magnetic glyconanoparticles

Current performance of iron oxide nanoparticle-based contrast agents in clinical use is based on the unspecific accumulation of the probes in certain organs or tissues. Specific targeted biofunctional nanoparticles would significantly increase their potential as diagnostic and therapeutic tools in vivo. In this study, multimodal fluorescent/magnetic glyco-nanoparticles were synthesized from gold-coated magnetite (glyco-ferrites) and converted into specific probes by the covalent coupling of protein G and subsequent incubation with an IgG antibody. The immuno-magnetic-fluorescent nanoparticles were applied to the specific labelling of peripheral blood mononuclear cells (PBMCs) in a complex biological medium, as human blood. We have been able to label specifically PBMCs present in blood in a percentage as low as 0.10–0.17%. Red blood cells (RBCs) were also clearly labelled, even though the inherent T 2 contrast arising from the high iron content of these cells (coming mainly from haemoglobin). The labelling was further assessed at cellular level by fluorescence microscopy. In conclusion, we have developed new contrast agents able to label specifically a cell population under adverse biological conditions (low abundance, low intrinsic T 2, high protein content). These findings open the door to the application of these probes for the labelling and tracking of endogenous cell populations like metastatic cancer cells, or progenitor stem cells that exist in very low amount in vivo.

Nanotechnology Development and Utilization: A Primer for Diagnostic and Interventional Radiologists

The term nanotechnology refers to the design, creation, and manipulation of structures on the nanometer scale. Much of the ongoing research and development of nanotechnology is focused on the development of novel methods of imaging and delivery of therapeutics through minimally invasive means. Multifunctional nanoparticles offer great promise for molecular imaging and directing novel therapeutics to molecular targets, which was never before possible. Nanoparticle-based contrast agents have been developed for all imaging modalities. A rapidly increasing number of companies and government funding initiatives have led to a large number of novel agents in various stages of development, ranging from in vitro and in vivo animal studies to clinical use. However, barriers to the delivery of nanoparticles for tumor imaging and therapy exist. Interventional radiologists may circumvent these barriers by using imaging to guide delivery of nanoparticles.