Nanoparticle Contrast Research Articles

Nanotechnology and osteoarthritis; part 1: Clinical landscape and opportunities for advanced diagnostics.

Osteoarthritis (OA) is a disease of the entire joint, often triggered by cartilage injury, mediated by a cascade of inflammatory pathways involving a complex interplay among metabolic, genetic, and enzymatic factors that alter the biochemical composition, microstructure, and biomechanical performance. Clinically, OA is characterized by degradation of the articular cartilage, thickening of the subchondral bone, inflammation of the synovium, and degeneration of ligaments that in aggregate reduce joint function and diminish quality of life. OA is the most prevalent joint disease, affecting 140 million people worldwide; these numbers are only expected to increase, concomitant with societal and financial burden of care. We present a two-part review encompassing the applications of nanotechnology to the diagnosis and treatment of OA. Herein, part 1 focuses on OA treatment options and advancements in nanotechnology for the diagnosis of OA and imaging of articular cartilage, while part 2 (10.1002/jor.24842) summarizes recent advances in drug delivery, tissue scaffolds, and gene therapy for the treatment of OA. Specifically, part 1 begins with a concise review of the clinical landscape of OA, along with current diagnosis and treatments. We next review nanoparticle contrast agents for minimally invasive detection, diagnosis, and monitoring of OA via magnetic resonace imaging, computed tomography, and photoacoustic imaging techniques as well as for probes for cell tracking. We conclude by identifying opportunities for nanomedicine advances, and future prospects for imaging and diagnostics.

Imaging the Thermal Hysteresis of Single Spin-Crossover Nanoparticles.

The magnetic hysteresis property during the spin transition of spin-crossover (SCO) materials holds great promise for their applications in spin electronics, information storage, thermochromic, and nanophotonic devices. Existing studies often measured the averaged property of a bulk sample consisting of lots of individuals. When considering the significant heterogeneity among different individuals and the inevitable interparticle interactions, ensemble measurement not only blurred the structure-property relationship but also compromised the intrinsic hysteresis property and cyclability. Herein, we employed a recently developed surface plasmon resonance microscopy (SPRM) method to measure the thermal hysteresis curve of single isolated SCO nanoparticles. The thermal-induced spin transition was found to alter the optical contrast of single SCO nanoparticles, which was optically readout using SPRM in a quantitative, nonintrusive, and high-throughput manner. Single nanoparticle measurements revealed an intrinsic transition temperature that was independent of the temperature scan rate and superior stability after over 11 000 cycles of single SCO nanoparticles. Correlations between the hysteresis and the size and morphology of the same individuals further uncovered the significant nanoparticle-to-nanoparticle heterogeneity with implications for the size-property relationship and rational design of SCO materials with improved performance.

Rapid event-related, BOLD fMRI, non-human primates (NHP): choose two out of three

Human functional magnetic resonance imaging (fMRI) typically employs the blood-oxygen-level-dependent (BOLD) contrast mechanism. In non-human primates (NHP), contrast enhancement is possible using monocrystalline iron-oxide nanoparticles (MION) contrast agent, which has a more temporally extended response function. However, using BOLD fMRI in NHP is desirable for interspecies comparison, and the BOLD signal’s faster response function promises to be beneficial for rapid event-related (rER) designs. Here, we used rER BOLD fMRI in macaque monkeys while viewing real-world images, and found visual responses and category selectivity consistent with previous studies. However, activity estimates were very noisy, suggesting that the lower contrast-to-noise ratio of BOLD, suboptimal behavioural performance, and motion artefacts, in combination, render rER BOLD fMRI challenging in NHP. Previous studies have shown that rER fMRI is possible in macaques with MION, despite MION’s prolonged response function. To understand this, we conducted simulations of the BOLD and MION response during rER, and found that no matter how fast the design, the greater amplitude of the MION response outweighs the contrast loss caused by greater temporal smoothing. We conclude that although any two of the three elements (rER, BOLD, NHP) have been shown to work well, the combination of all three is particularly challenging.

Real-Time Imaging of Cell Therapy with Acoustics

Background & Aim Cell therapy has shown significant promise in treating disease. Unfortunately, stem cell therapy is limited by mis-injection into highly fibrotic tissues, poor cell survival due to ischemia and inflammation, and low cell retention. For these reasons, our group has developed a variety of tools that facilitae real-time imaging of stem cell therapy. We are particualrly intersted in acoustic and photoacoustic imaging because of their low cost, ease of use, and video frame rates to faciliate real-time imaging of the cell delivery event as well as downstream analysis of cell biodistribution. We have built several novel nanoparticles contrast agents and used them image mesenchymal stem cell delivery and location in vivo. These same nanoparticles can often also provide MRI signal or deliver pro-survival drugs in addition to reporting the location of the therapeutic cells. Methods, Results & Conclusion Here, I will discuss the value of acoustic imaging as applied to cell therapy using cardiac cell therapy as an example. This work used a biocompatible multi-functional silica-iron oxide nanoparticle (SIO) made via an in situ growth of Fe3O4 nanoparticles on both the external surfaces and pore walls of mesocellular foam silica nanoparticles. In contrast to prior work, this approach builds a magnetic moiety inside the pores of a porous silica structure. These materials serve three roles: drug delivery, magnetic manipulation, and imaging. The addition of Fe3O4 to the silica nanoparticles increased their colloidal stability, T2-based magnetic resonance imaging (MRI) contrast, and superparamagnetism. The particle core offered acousticv signal. We then used the hybrid materials as a sustained release vehicle of insulin-like growth factor—a pro-survival agent that can increase cell viability. In vivo rodent studies show that labeling stem cells with this nanoparticle increased the efficacy of stem cell therapy in a ligation/reperfusion model. The nanoparticle-labeled cells increase the mean left ventricular ejection fraction by 11% and 21% and the global longitudinal strain by 24% and 34% on days 30 and 60, respectively. In summary, this multifunctional nanomedicine improves stem cell survival via the sustained release of pro-survival agents.

Time-course study of a gold nanoparticle contrast agent for cardiac-gated micro-CT imaging in mice

Although micro-computed tomography (micro-CT) images have high contrast for bone or air, between soft tissues the contrast is typically low. To overcome this inherent issue, attenuating exogenous contrast agents are used to provide contrast enhancement in the vasculature and abdominal organs. The aim of this study is to measure the contrast enhancement time course for a gold nanoparticle blood-pool contrast agent and use it to perform cardiac-gated 4D micro-CT scans of the heart. Six healthy female C57BL/6 mice were anesthetized and imaged after receiving an injected dose of MVivo gold nanoparticle blood-pool contrast agent. Following the injection, we performed micro-CT scans at 0, 0.25, 0.5, 0.75, 1, 2, 4, 8, 24, 48 and 72 h. The mean CT number was measured for 7 different organs. No contrast enhancement was noticed in the bladder, kidneys or muscle during the time-course study. However, it clearly appears that the contrast enhancement is high in both right ventricle and vena cava. To perform cardiac-gated imaging, either the gold nanoparticle agent (n = 3) or an iodine-based (n = 3) contrast agent was introduced and images representing 9 phases of the cardiac cycle were obtained in 6 additional mice. A few typical cardiac parameters were measured or calculated, with similar accuracy between the gold and iodinated agents, but better visualization of structures with the gold agent. The MVivo Au contrast agent can be used for investigations of cardiac or vascular disease with a single bolus injection, with an optimal cardiac imaging window identified during the first hour after injection, demonstrating similar image quality to iodinated contrast agents and excellent measurement accuracy. Furthermore, the long-lasting contrast enhancement of up to 8 h can be very useful for scanning protocols that require longer acquisition times.

Recent Advances of Bioresponsive Nano-Sized Contrast Agents for Ultra-High-Field Magnetic Resonance Imaging.

The ultra-high-field magnetic resonance imaging (MRI) nowadays has been receiving enormous attention in both biomaterial research and clinical diagnosis. MRI contrast agents are generally comprising of T1-weighted and T2-weighted contrast agent types, where T1-weighted contrast agents show positive contrast enhancement with brighter images by decreasing the proton's longitudinal relaxation times and T2-weighted contrast agents show negative contrast enhancement with darker images by decreasing the proton's transverse relaxation times. To meet the incredible demand of MRI, ultra-high-field T2 MRI is gradually attracting the attention of research and medical needs owing to its high resolution and high accuracy for detection. It is anticipated that high field MRI contrast agents can achieve high performance in MRI imaging, where parameters of chemical composition, molecular structure and size of varied contrast agents show contrasted influence in each specific diagnostic test. This review firstly presents the recent advances of nanoparticle contrast agents for MRI. Moreover, multimodal molecular imaging with MRI for better monitoring is discussed during biological process. To fasten the process of developing better contrast agents, deep learning of artificial intelligent (AI) can be well-integrated into optimizing the crucial parameters of nanoparticle contrast agents and achieving high resolution MRI prior to the clinical applications. Finally, prospects and challenges are summarized.

Novel Method for Electroless Etching of 6H-SiC.

In this article, we report an electroless method to fabricate porous hexagonal silicon carbide and hexagonal silicon carbide nanoparticles (NPs) as small as 1 nm using wet chemical stain etching. We observe quantum confinement effect for ultrasmall hexagonal SiC NPs in contrast to the cubic SiC NPs. We attribute this difference to the various surface terminations of the two polytypes of SiC NPs.

Preparation and in vitro imaging of a magnetic heating phasetransition multimodal ultrasound contrast agent

Objective To prepare a novel magnetic heating phasetransition nanoparticle contrast agent (PFH-HIONS), and to study its performance on enhancing photoacoustic imaging, magnetic resonance imaging and ultrasound imaging after phasetransition by magnetic-thermo in vitro. Methods Firstly, the superparamagnetic nano hollow iron spheres (HIONS) were prepared by a one-pot solvothermal method, and then the phasetransition liquid perfluorocarbon (PFH) was loaded on the HIONS by vacuum adsorption to obtain PFH-HIONS. After characterization of the nanoparticles, photoacoustic imaging, magnetic resonance imaging and ultrasound imaging after phasetransition with magnetic-thermo were performed in vitro, and the results were analyzed by a software. Results PFH-HIONS was successfully prepared with uniform particle size of (537.3±24.8)nm. PFH-HIONS could apparently enhance photoacoustic imaging and magnetic resonance imaging in vitro. In an alternating magnetic field, it could significantly increase the temperature, which promotes phasetransion of the PFH to produce microbubbles, thereby enhancing ultrasound imaging. Furthermore, as the concentration increased, the imaging intensity was enhanced, and the differences in imaging intensity between different concentration groups were statistically significant (P<0.05). Conclusions The PFH-HIONS can enhance the multimodal imaging including ultrasound, photoacoustic and magnetic resonance, and it also has obvious magnetic heating performance. It provides a new and efficient research platform for theranostics based on molecular imaging, therefore it has promising application prospects. Key words: Magnetic heating; Phasetransition; Contrast agent; Multimodal

Role of Gd2O3-doped carbon-11-choline-lenvatinib nanoparticles contrast agent PET/CT in the diagnosis of patients with lung cancer.

Positron emission tomography-computed tomography (PET/CT) is an efficient method for the diagnosis of various types of human cancer. Studies have demonstrated that Gd2O3-doped carbon-11-choline (GdCho) can be used as a contrast nanoparticle for PET/CT in the diagnosis of patients with lung cancer. The aim of the present study was to evaluate the effect of GdCho-lenvatinib nanoparticles contrast-PET/CT (GdCho-Len-PET) in the diagnosis and treatment planning of a cohort of patients suspected of having lung cancer. The results of the present study demonstrated that GdCho-Len could be used as an efficient PET/CT contrast agent for the diagnosis of patients with lung cancer. GdCho-Len nanoparticles contrast agent exhibited a significantly improved longitudinal relaxivity compared with GdCho. The outcomes of the present study were that GdCho-Len-PET diagnosed 152 patients with lung cancer, whereas GdCho-PET diagnosed 130 patients with lung cancer among the 172 patients. GdCho-Len-PET presented with higher accuracy and sensitivity compared with GdCho-PET in diagnosing patients with lung cancer. All patients were further confirmed via histological analysis. GdCho-Len-PET contributed to the anticancer treatments in 56 out of 62 (90.3%) patients with lung cancer who were candidates for radiation therapy, 52 out of 57 (91.2%) patients with lung cancer undergoing adjuvant radiotherapy, and 13 out of 17 (76.5%) patients with lung cancer undergoing comprehensive therapy. Patients diagnosed using GdCho-Len-PET improved the survival of patients with lung cancer during a 420-day follow up. In conclusion, GdCho-Len-PET increased the diagnostic efficacy and had a significant effect on survival for patients with lung cancer, and may therefore serve as a reliable method for human cancer diagnosis.

Multi‐“Color” Delineation of Bone Microdamages Using Ligand‐Directed Sub‐5 nm Hafnia Nanodots and Photon Counting CT Imaging

AbstractThe early detection of bone microdamages is crucial to make informed decisions about the therapy and taking precautionary treatments to avoid catastrophic fractures. Conventional computed tomography (CT) imaging faces obstacles in detecting bone microdamages due to the strong self‐attenuation of photons from bone and poor spatial resolution. Recent advances in CT technology as well as novel imaging probes can address this problem effectively. Herein, the bone microdamage imaging is demonstrated using ligand‐directed nanoparticles in conjunction with photon counting spectral CT. For the first time, Gram‐scale synthesis of hafnia (HfO2) nanoparticles is reported with surface modification by a chelator moiety. The feasibility of delineating these nanoparticles from bone and soft tissue of muscle is demonstrated with photon counting spectral CT equipped with advanced detector technology. The ex vivo and in vivo studies point to the accumulation of hafnia nanoparticles at microdamage site featuring distinct spectral signal. Due to their small sub‐5 nm size, hafnia nanoparticles are excreted through reticuloendothelial system organs without noticeable aggregation while not triggering any adverse side effects based on histological and liver enzyme function assessments. These preclinical studies highlight the potential of HfO2‐based nanoparticle contrast agents for skeletal system diseases due to their well‐placed K‐edge binding energy.

Nanotechnology in Oral Cavity Carcinoma: Recent Trends and Treatment Opportunities.

Oral cavity carcinoma (OCC) remains an ongoing public health problem. Emerging nanotechnology provides alternative treatment approaches. This review covers the up-to-date literature in the human OCC treatment field. We explored the growing body of evidence to reveal novel and highly promising diagnostic and therapeutic applications of nanotechnology in this field. Various types of nanoparticles have been tested for applications in OCC. Imaging modalities in addition to nanocarriers are discussed. The encouraging contribution of lymphotropic nanoparticles contrast in the diagnosis of metastatic cervical lymph nodes needs to be confirmed. The development of the sentinel lymph node procedure and photodynamic therapy may lead to breakthrough therapies in order improve clinical outcomes and quality of life. In this perspective, cancer nanotechnology has the potential to revolutionize the treatment of OCC patients.

Precisely Tuning the Contrast Properties of ZnxFe3–xO4 Nanoparticles in Magnetic Resonance Imaging by Controlling Their Doping Content and Size

Given that the contrast of Zn-doped Fe3O4 nanoparticles (NPs) (ZnxFe3–xO4) in magnetic resonance imaging (MRI) depends on their intrinsic chemical and physical properties such as doping content or ...

Theranostic Calcium Phosphate Nanoparticles With Potential for Multimodal Imaging and Drug Delivery.

Calcium phosphate (CaP) bioceramics closely resemble the natural human bone, which is a main reason for their popularity as bone substitutes. However, this compositional similarity makes it difficult to distinguish CaPs, especially in particulate form, from native bone by imaging modalities such as X-ray radiography, computed tomography (CT), and magnetic resonance imaging (MRI) to monitor the healing progress. External contrast agents can improve the imaging contrast of CaPs but can affect their physicochemical properties and can produce artifacts. In this work, we have attempted to improve the contrast of CaP nanoparticles via ion substitutions for multimodal imaging. Calcium-deficient hydroxyapatite (CDHA) nanoparticles with silver (Ag), gadolinium (Gd), and iron (Fe) substitution were prepared by a microwave-accelerated wet chemical process to improve the contrast in CT, T1 (spin–lattice), and T2 (spin–spin) MRI relaxation modes, respectively. Ag, Gd, and Fe were substituted at 0.25, 0.5, and 0.25 at.%, respectively. The ion-substituted CDHA (ICDHA) was found to be phase pure by X-ray diffraction (XRD) and Fourier transform infrared spectroscopy (FT-IR). Transmission electron microscopy (TEM) images showed that the ICDHA nanoparticles were platelet shaped and of 52 ± 2 nm length and 6 ± 1 nm width. The ICDHA showed high contrast in X-ray and CT compared to CDHA. The vibrating sample magnetometry (VSM) studies showed the ICDHA to exhibit paramagnetic behavior compared to diamagnetic CDHA, which was further confirmed by improved contrast in T1 and T2 MRI mode. In addition, the in vitro tetracycline drug loading and release was studied to investigate the capability of these nanoparticles for antibiotic drug delivery. It was found that a burst release profile was observed for 24 h with 47–52% tetracycline drug release. The ICDHA nanoparticles also showed in vitro antibacterial activity against Staphylococcus aureus and Escherichia coli due to Ag, which was further enhanced by antibiotic loading. In vitro biocompatibility studies showed that the triple-ion-substituted ICDHA nanoparticles were cytocompatible. Thus, the ion-substituted CDHA nanoparticles can have potential theranostic applications due to their multimodal image contrast, antibacterial activity, and drug delivery potential. Future work will be conducted with actual bone samples in vitro or in animal models.

Technical Note: The first live treatment on a 1.0 Tesla inline MRI-linac.

This work describes the first live imaging and radiation delivery performed on a prototype 1.0T inline MRI-Linac system in a rat brain tumor model, which was conducted on 29 January 2019. A human scale 1.0T MRI-Linac was adapted to be suitable for animal studies via a specially constructed open 6-channel receiver radiofrequency (RF) coil. A Fischer rat injected with 9L glioma cells in the right hemisphere was imaged and irradiated at day 11 post surgery as part of a larger cohort survival study. The rat was anesthetized and positioned at the iscocenter of the MRI-Linac. Imaging was used to localize the brain and confirm the presence of a tumor following the administration of a gadolinium nanoparticle contrast agent. A single dose of 10Gy was delivered using a 2.25cm×2.90cm radiation field covering the whole brain and verified with radiosensitive film insitu. Real-time imaging was used throughout the irradiation period to monitor the animal and target position. The signal-to-noise ratio (SNR) measured in the rat brain was 38. Postcontrast imaging was able to demonstrate a tumor of 5mm diameter in the upper right hemisphere of the brain approximately 45min after administration of the nanoparticles. The radiation beam had no impact on SNR and images at the rate of 2Hz were effective in monitoring both respiration and intrafractional motion. In vivo film dosimetry confirmed the intended dose delivery. The total procedure time was 35min. We have successfully used MRI guidance to localize and subsequently deliver a radiation field to the whole brain of a rat with a right hemispheric tumor. Real-time imaging during beam on was of sufficient quality to monitor breathing and perform exception gating of the treatment. This represents the first live use of a high field inline MRI-Linac.

Targeted Gold Nanoparticle⁻Oligonucleotide Contrast Agents in Combination with a New Local Voxel-Wise MRI Analysis Algorithm for In Vitro Imaging of Triple-Negative Breast Cancer.

Gold nanoparticles (GNPs) have tremendous potential as cancer-targeted contrast agents for diagnostic imaging. The ability to modify the particle surface with both disease-targeting molecules (such as the cancer-specific aptamer AS1411) and contrast agents (such as the gadolinium chelate Gd(III)-DO3A-SH) enables tailoring the particles for specific cancer-imaging and diagnosis. While the amount of image contrast generated by nanoparticle contrast agents is often low, it can be augmented with the assistance of computer image analysis algorithms. In this work, the ability of cancer-targeted gold nanoparticle–oligonucleotide conjugates to distinguish between malignant (MDA-MB-231) and healthy cells (MCF-10A) is tested using a T1-weighted image analysis algorithm based on three-dimensional, deformable model-based segmentation to extract the Volume of Interest (VOI). The gold nanoparticle/algorithm tandem was tested using contrast agent GNP-Gd(III)-DO3A-SH-AS1411) and nontargeted c-rich oligonucleotide (CRO) analogs and control (CTR) counterparts (GNP-Gd(III)-DO3A-SH-CRO/CTR) via in vitro studies. Remarkably, the cancer cells were notably distinguished from the nonmalignant cells, especially at nanomolar contrast agent concentrations. The T1-weighted image analysis algorithm provided similar results to the industry standard Varian software interface (VNMRJ) analysis of T1 maps at micromolar contrast agent concentrations, in which the VNMRJ produced a 19.5% better MRI contrast enhancement. However, our algorithm provided more sensitive and consistent results at nanomolar contrast agent concentrations, where our algorithm produced ~500% better MRI contrast enhancement.

Detecting the propped fracture by injection of magnetic proppant during fracturing

Hydraulic fracturing is key to enhancing the productivity of shale and tight hydrocarbon reservoirs, as well as geothermal resources from hot dry rock. Assessing the range and efficiency of hydraulic fracturing is very important for onsite fracturing operations and decision making on subsequent fracturing plans and well-pattern deployment. The idea of injecting fluid mixed with magnetic material into a formation to detect subterranean structure has been considered for a long time. The detectability of the characteristics of propped fractures using magnetic field measurement is discussed and evaluated with an analytical model. The magnetic proppants synthesized with superparamagnetic nanoparticles should be “silent” during injection and could be activated by an external current. By measuring the magnetic field before and after the fracture was created and the magnetic proppants were magnetized, the magnetic anomalies can be obtained. The result indicates that the magnetic field caused by a fracture filled with magnetic proppants is very weak, so that magnetometers with higher precision and resolution should be used to capture such subtle signal. The higher susceptibility contrast of the magnetic nanoparticles is, the stronger external magnetic induction field could be detected. It is suggested that the superparamagnetic nanomaterial with effective magnetic susceptibility contrast of greater than 0.4–0.5 should be used for fracture monitoring in deep wells. To infer the fracture characteristics with the magnetic anomaly, the ground and adjacent wells’ monitoring practices are recommended.

Trimodal Nanoparticle Contrast Agent for CT, MRI and SPECT Imaging: Synthesis and Characterization of Radiolabeled Core/Shell Iron Oxide@Gold Nanoparticles

Recently, nanoparticles have emerged as promising contrast agents for various imaging applications. In this paper, we present the synthesis and characterization of a novel hybrid nano-structure, co...

Functional imaging of tumor vasculature using iodine and gadolinium-based nanoparticle contrast agents: a comparison of spectral micro-CT using energy integrating and photon counting detectors

Advances in computed tomography (CT) hardware have propelled the development of novel CT contrast agents. In particular, the spectral capabilities of x-ray CT can facilitate simultaneous imaging of multiple contrast agents. This approach is particularly useful for functional imaging of solid tumors by simultaneous visualization of multiple targets or architectural features that govern cancer development and progression. Nanoparticles are a promising platform for contrast agent development. While several novel imaging moieties based on high atomic number elements are being explored, iodine (I) and gadolinium (Gd) are particularly attractive because of their existing approval for clinical use. In this work, we investigate the in vivo discrimination of I and Gd nanoparticle contrast agents using both dual energy micro-CT with energy integrating detectors (DE-EID) and photon counting detector (PCD)-based spectral micro-CT. Simulations and phantom experiments were performed using varying concentrations of I and Gd to determine the imaging performance with optimized acquisition parameters. Quantitative spectral micro-CT imaging using liposomal-iodine (Lip-I) and liposomal-Gd (Lip-Gd) nanoparticle contrast agents was performed in sarcoma bearing mice for anatomical and functional imaging of tumor vasculature. Iterative reconstruction provided high sensitivity to detect and discriminate relatively low I and Gd concentrations. According to the Rose criterion applied to the experimental results, the detectability limits for I and Gd were approximately 2.5 mg ml−1 for both DE-EID CT and PCD micro-CT, even if the radiation dose was approximately 3.8 times lower with PCD micro-CT. The material concentration maps confirmed expected biodistributions of contrast agents in the blood, liver, spleen and kidneys. The PCD provided lower background signal and better simultaneous visualization of tumor vasculature and intratumoral distribution patterns of nanoparticle contrast agent compared to DE-EID decompositions. Preclinical spectral CT systems such as this could be useful for functional characterization of solid tumors, simultaneous quantitative imaging of multiple targets and for identifying clinically-relevant applications that benefit from the use of spectral imaging. Additionally, it could aid in the development nanoparticles that show promise in the developing field of cancer theranostics (therapy and diagnostics) by measuring vascular tumor biomarkers such as fractional blood volume and the delivery of liposomal chemotherapeutics.

Evaluation of X‐ray tomography contrast agents: A review of production, protocols, and biological applications

X-ray computed tomography is a strong tool that finds many applications both in medical applications and in the investigation of biological and nonbiological samples. In the clinics, X-ray tomography is widely used for diagnostic purposes whose three-dimensional imaging in high resolution helps physicians to obtain detailed image of investigated regions. Researchers in biological sciences and engineering use X-ray tomography because it is a nondestructive method to assess the structure of their samples. In both medical and biological applications, visualization of soft tissues and structures requires special treatment, in which special contrast agents are used. In this detailed report, molecule-based and nanoparticle-based contrast agents used in biological applications to enhance the image quality were compiled and reported. Special contrast agent applications and protocols to enhance the contrast for the biological applications and works to develop nanoparticle contrast agents to enhance the contrast for targeted drug delivery and general imaging applications were also assessed and listed.

Nanoparticle contrast-enhanced micro-CT: A preclinical tool for the 3D imaging of liver and spleen in longitudinal mouse studies

In drug discovery and development, X-ray micro-computed tomography (micro-CT) has gained increasing importance over the past decades. In recent years, micro-CT imaging of soft tissues has become popular due to the introduction of a variety of radiopaque contrast agents. More recently, nanoparticle-based ExiTron nano 12,000 has become commercially available for the nonclinical micro-CT imaging of soft tissues in rodents. Phagocytosis and accumulation of the contrast agent by Kupffer cells in the liver, as well as macrophages in the spleen, increase the soft tissue X-ray attenuation for up to 6 months. Therefore, it is essential to understand the potential toxicity of this nanomaterial in micro-CT imaging prior to its application in pharmacology and/or toxicology studies. Herein, we describe the time-course and distribution of the contrast in the liver, spleen and blood after a single intravenous injection (IV) of this nanoparticle contrast agent at 0.1 ml/mouse. Thoracic images of male adult C57BL/6 mice were acquired using a Bruker SkyScan 1276 micro-CT over a period of 29 days. The stability of X-ray attenuation enhancement in the above tissues was also tested after a single dose of Kupffer cell toxicant gadolinium chloride (GdCl3) at 15 mg/kg on day 2. The liver, spleen and kidney were examined microscopically on days 15 and 29 post treatment. Serum and liver cytokines (IL-1β, IL-2, IL-6, IL-10, IL-12p70, IFN-γ, IP-10, MIP1-α, MIP1-β and TNF-α) were quantified on days 15 and 29 as indicators of a pro-inflammatory response to treatment. This study determined that there was an accumulation of amphophilic granular material in the cells of the mononuclear phagocyte system in the liver and spleen following a single dose of ExiTron nano 12,000 and a second dose of GdCl3 or its vehicle. However, ExiTron nano12000 contrast administration did not cause any hepatotoxicity in the liver, nor did pro-inflammatory cytokines release in the liver or serum. Similarly, there were no adverse pathologies in the spleen or kidneys. In summary, ExiTron nano12000 contrast agent-enhanced micro-CT could be used as a safe method in up to 29-day longitudinal efficacy and toxicology mouse studies for the non-invasive assessment of the liver and spleen.