Inflammatory bowel disease (IBD) affects approximately 3.1 million individuals in the U.S., causing deleterious symptoms such as bloody diarrhea and leading to an increased risk of colorectal cancer. Effective imaging is crucial for diagnosing and managing IBD, as it allows for accurate assessment of disease severity, guides treatment decisions, and monitors therapeutic responses. Computed tomography (CT) with contrast agents is the gold standard for imaging the gastrointestinal tract (GIT). However, current agents are less effective in obese patients and lack specificity for inflamed regions associated with IBD. Moreover, IBD treatments often have limited efficacy and do not address the role of oxidative stress in IBD progression. This study explores dextran-coated cerium oxide nanoparticles (Dex-CeNP) as a CT contrast agent and therapeutic for IBD, leveraging cerium's superior K-edge energy profile, dextran's inflammation-specific targeting, and cerium oxide's antioxidant properties. Herein, we synthesized Dex-CeNP formulations using 5, 10, 25, and 40 kDa dextran to explore the effect of dextran coating molecular weight. In vitro assays showed formulation biocompatibility and demonstrated that 5 kDa Dex-CeNP had the highest catalytic activity, which translated into improved suppression of inflammation. As a result, this formulation was selected for in vivo use. In vivo CT imaging of mice subjected to dextran sodium sulfate (DSS) colitis showed that Dex-CeNP provided better contrast in the GIT of mice with colitis compared to iopamidol (ISO), with pronounced attenuation in the large intestine and disease- specific retention at 24 h. Additionally, Dex-CeNP significantly decreased Disease Activity Index (DAI) scores, and diminished gastrointestinal bleeding when compared with a currently approved drug, indicating that it is an effective treatment for colitis. Studies also revealed that the Dex-CeNPs were safe and well-excreted following administration. In summary, Dex-CeNP has significant promise as a dual-purpose agent for CT imaging and treatment of IBD.

Purpose: To compare the effectiveness of transarterial embolization (TAE) using a liquid embolic (LE) with that of TAE using a particle embolic (PE) based on radiographic and histologic responses in a translational rat model of hepatocellular carcinoma (HCC). Materials and Methods: HCC was induced in Wistar rats using diethylnitrosamine. Tumor response was determined through Response Evaluation Criteria in Solid Tumors applied to T2-weighted magnetic resonance (MR) imaging scans. Tumor necrosis and hypoxia were assessed through hematoxylin and eosin and pimonidazole staining, respectively. Statistical analyses were performed using chi-square tests, Kaplan-Meier estimates, logistic regression, and 1-way analysis of variance, with significance set at P < .05. Results: Twenty-nine rats were randomized to TAE with LE (n = 13), PE (n = 13), or sham (n = 3). LE TAE demonstrated a significantly higher objective response rate (83%) compared with PE TAE (28%; chi(2) =11.25; P = .0008). Complete responses were observed in 50% of the LE-treated tumors versus 10% in the PE-treated group. LE TAE prolonged local progression-free survival (hazard ratio, 0.31; P = .032). Histologic analysis of an additional 16 rats randomized to TAE with LE (n = 7), PE (n = 6), or sham (n = 3) showed greater necrosis in LE-treated tumors compared to PE-treated tumors. LE induced a significantly greater reduction in viable tumor tissue (P = .009) and proportionally larger necrotic and necrotic + hypoxic tissue areas compared with PE (P = .003). Conclusions: LE significantly enhanced the therapeutic effectiveness of TAE in a rat model of HCC compared with PE. These results highlight the potential of LEs to improve ischemia and necrosis, thereby offering a promising option for improving the effectiveness of embolization for HCC treatment.

Purpose:To evaluate the feasibility and performance of K-edge imaging of iodine (I) and gadolinium (Gd) on a clinically available photon-counting computed tomography (PCCT) system. Methods:A dual-source clinical PCCT scanner with four energy thresholds (20, 55, 72, 90 keV) was used to scan phantoms containing pure and mixed solutions of I and Gd across multiple concentrations (1-10 mg/mL) and radiation doses (1-8 mGy). Multi-material decomposition was performed using a calibration-based, image-domain algorithm to generate material-specific maps. Quantitative accuracy was assessed using Bland-Altman analysis and contrast-to-noise ratio (CNR), while noise and bias trends were statistically analyzed using non-parametric tests. Results:K-edge imaging was successfully achieved on a clinical PCCT system with accurate decomposition of I and Gd across varying concentrations, solution types (pure/mixed), and dose levels. Quantitative bias was significantly influenced by radiation dose, concentration, and solution type (p < 0.0004). Increased radiation dose and contrast concentration improved quantification accuracy, with maximum bias reductions of 0.9 (I) and 0.3 mg/mL (Gd). CNR correlated linearly with concentration (R2 > 0.99) and moderately with dose (R2 = 0.85-0.94), achieving peak values of 13 (I) and 16 (Gd) at 8 mGy. Mixed solutions showed reduced performance compared to pure solutions, i.e., CNR of 5 mg/mL Gd solutions increased by 0.6 per mGy in pure solutions while by 0.5 per mGy in mixtures. Noise was dependent on dose but not on concentration or solution type. Conclusion:This study establishes the feasibility of K-edge imaging using a clinical PCCT system and demonstrates accurate, simultaneous decomposition of I and Gd in pure and mixed solutions. These findings support the clinical translation of K-edge imaging and highlight PCCT's potential for advanced dual-contrast and molecular imaging applications.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease (IBD). CT imaging with contrast agents is commonly used for visualizing the gastrointestinal (GI) tract in UC patients. Contrast agents that provide enhanced imaging performance are highly valuable in this field. Recent studies have made significant progress in developing better contrast agents for imaging the gastrointestinal tract using nanoparticles. However, the impact of nanoparticle size on this application remains unexplored. Gold nanoparticles (AuNPs) serve as an ideal model to investigate the effect of nanoparticle size on imaging of the gastrointestinal tract due to their controllable synthesis across a broad size range. In this study, we synthesized AuNPs with core sizes ranging from 5 to 75 nm to examine the effect of the size in this setting. AuNPs were coated with poly(ethylene glycol) (PEG) to enhance stability and biocompatibility. In vitro tests show that gold nanoparticles are cytocompatible with macrophage cells (∼100% cell viability) and remain stable under acidic conditions, with no significant size changes over time. Phantom imaging studies using a clinical CT scanner indicated that there was no effect of nanoparticle size on CT contrast production, as previously demonstrated. In vivo imaging using a mouse model of acute colitis revealed a strong contrast generation throughout the GI tract for all agents tested. For the most part, in vivo contrast was independent of AuNP size, although AuNP outperformed iopamidol (a clinically approved control agent). In addition, differences in attenuation trends were observed between healthy and colitis mice. We also observed almost complete clearance at 24 h of all formulations tested (less than 0.7% ID/g was retained), supporting their value as a model platform for studying nanoparticle behavior in imaging. In conclusion, this study highlights the potential of nanoparticles as effective contrast agents for CT imaging of the gastrointestinal tract (GIT) in the UC. Further systemic research is needed to explore contrast agents that can specifically image disease processes in this disease setting.

Breast cancer is one of the most common types of cancer, however, preventive screening has contributed to a significant reduction in mortality over the past four decades. The first-line screening methods for breast cancer, such as mammography and tomosynthesis, are x-ray-based modalities. Unfortunately, their cancer detection rates are low in patients with dense breasts. These, and other high-risk women, are now encouraged to receive supplemental screening. The supplemental imaging methods are diverse, including ultrasound, MRI, nuclear imaging, and X-ray-based modalities such as breast CT and contrast-enhanced mammography/tomosynthesis. Due to their low cost and wide availability, x-ray-based modalities see significant clinical use worldwide. These techniques benefit from the use of contrast agents, which are currently iodinated small molecules designed for other purposes. Consequently, developing new contrast agents that are specifically for breast cancer screening is of interest. This review describes these modalities and the nanoparticle-based contrast agents being researched for their enhanced performance. The relevant parameters for nanoparticle-based contrast agent design are evaluated, including contrast generation and potential biointeractions. Iodinated agents are discussed for comparison. Nanoparticles covered include silver sulfide, silver telluride, gold, and bismuth sulfide-based agents, among others. Finally, perspectives on future developments in this field are offered.

Compared with conventional mammography, contrast-enhanced dual-energy mammography (DEM) can improve tumor detection for people with dense breasts. However, currently available iodine-based contrast agents have several drawbacks such as their contraindication for use with renal insufficiency, high-dose requirement, and suboptimal contrast production. Molybdenum disulfide nanoparticles (MoS2 NPs) have been shown to attenuate X-rays due to molybdenum's relatively high atomic number while having good biocompatibility. However, work exploring their use as X-ray contrast agents has been limited. In this study, we have developed a novel aqueous synthesis yielding ultrasmall, 2 nm MoS2 NPs with various small molecule coatings, including glutathione (GSH), penicillamine, and 2-mercaptopropionic acid (2MPA). These nanoparticles were shown to have low in vitro cytotoxicity when tested with various cell lines at concentrations up to 1 mg/mL. For the first time, these particles were shown to generate clinically relevant contrast in DEM. In DEM, MoS2 NPs generated higher contrast than iopamidol, a commercially available X-ray contrast agent, while also generating substantial contrast in CT. Moreover, MoS2 NPs demonstrated rapid elimination in vivo, mitigating long-term toxicity concerns. Together, the results presented here suggest the potential utility of MoS2 NPs as a dual-modality X-ray contrast agent for DEM and CT.

Purpose To compare the effectiveness of transarterial embolization (TAE) using a liquid embolic (LE) to TAE using particle embolics (PE) with respect to tumor ischemia and treatment response in a translational rat model.Materials and Methods HCC was induced in male Wistar rats using diethylnitrosamine. Rats were randomized into three treatment groups: sham transarterial embolization (TAE), TAE with LE, and TAE with PE. Tumor response to TAE was monitored via serial T2-weighted MRI scans and assessed using RECIST. Tumor necrosis and hypoxia were assessed through hematoxylin and eosin staining and pimonidazole immunohistochemistry, respectively. Statistical analyses were performed using chi-square tests, Kaplan-Meier estimates, and one-way ANOVAs, with significance set at p<0.05.Results Twenty-nine rats were randomized to TAE with LE (n=13), PE (n=13), or sham (n=3). TAE with LE demonstrated a significantly higher objective response rate (83%) compared to TAE with PE (28%; χ2 = 11.25, P=0.0008). Complete responses were observed in 50% of the LE-treated tumors versus 10% in the PE-treated group. LE treatment prolonged local progression-free survival (hazard ratio = 0.23; p=0.0085). Histological analysis, with an additional 14 rats randomized to TAE with LE (n=5), PE (n=6), or sham (n=3), showed greater necrosis and hypoxia in LE-treated tumors compared to PE. LE induced a significant reduction in viable tumor tissue (p<0.05) and increased necrotic and hypoxic tissue areas compared to PE (p<0.01).Conclusion LE significantly enhanced the therapeutic efficacy of TAE in a rat model of HCC compared to conventional PE. The results highlight LE’s potential to improve ischemia and necrosis, thereby offering a promising option improving the efficacy of embolization for HCC treatment.### Competing Interest StatementResearch grant from Instylla LLC

Ultrasmall silver sulfide nanoparticles (Ag 2 S-NP) have been identified as promising contrast agents for a number of modalities and in particular for dual-energy mammography. These Ag 2 S-NP have demonstrated marked advantages over clinically available agents with the ability to generate higher contrast with high biocompatibility. However, current synthesis methods are low-throughput and highly time-intensive, limiting the possibility of large animal studies or eventual clinical use of this potential imaging agent. We herein report the use of a scalable silicon microfluidic system (SSMS) for the large-scale synthesis of Ag 2 S-NP. Using SSMS chips with 1 channel, 10 parallelized channels, and 256 parallelized channels, we determined that the Ag 2 S-NP produced were of similar quality as measured by core size, concentration, UV-visible spectrometry, and in vitro contrast generation. Moreover, by combining parallelized chips with increasing reagent concentration, we were able to increase output by an overall factor of 3,400. We also found that in vivo imaging contrast generation was consistent across synthesis methods and confirmed renal clearance of the ultrasmall nanoparticles. Finally, we found best-in-class clearance of the Ag 2 S-NP occurred within 24 hours. These studies have identified a promising method for the large-scale production of Ag 2 S-NP, paving the way for eventual clinical translation.

Bacterial biofilms are pervasive and recalcitrant to current antimicrobials, causing numerous infections. Iron oxide nanozymes, including an FDA-approved formulation, ferumoxytol (FMX), show potential against biofilm infections via catalytic activation of hydrogen peroxide (H2O2). However, clinical evidence regarding the efficacy and therapeutic mechanisms of FMX is lacking. Here, we investigate whether FMX nanozymes can treat chronic biofilm infections and compare their bioactivity to that of the gold standard sodium hypochlorite (NaOCl), a potent but caustic disinfectant. Clinical performance was assessed in patients with apical periodontitis, an intractable endodontic infection affecting half of the global adult population. Data show robust antibiofilm activity by a single application of FMX with H2O2 achieving results comparable to those seen with NaOCl without adverse effects. FMX binds efficiently to the bacterial pathogens Enterococcus faecalis and Fusobacterium nucleatum and remains catalytically active without being affected by dental tissues. This allows for effective eradication of endodontic biofilms via on-site free radical generation without inducing cytotoxicity. Unexpectedly, FMX promotes growth of stem cells of the apical papilla (SCAPs), with transcriptomic analyses revealing upregulation of proliferation-associated pathways and downregulation of cell cycle suppressor genes. Notably, FMX activates SCAP pluripotency and WNT/NOTCH signaling that induces its osteogenic capacity. Together, these results show that FMX nanozymes are clinically effective against severe chronic biofilm infection with pathogen targeting and unique stem cell- stimulatory properties, offering a regenerative approach to antimicrobial therapy.

Bacterial infections in irregular and branched confinements pose significant therapeutic challenges. Despite their high antimicrobial efficacy, enzyme-mimicking nanoparticles (nanozymes) face difficulties in achieving localized catalysis at distant infection sites within confined spaces. Incorporating nanozymes into microrobots enables the delivery of catalytic agents to hard-to-reach areas, but poor nanoparticle dispersibility and distribution during fabrication hinder their catalytic performance. To address these challenges, a nanozyme-shelled microrobotic platform is introduced using magnetic microcapsules with collective and adaptive mobility for automated navigation and localized catalysis within complex confinements. Using double emulsions produced from microfluidics as templates, iron oxide and silica nanoparticles are assembled into 100-µm microcapsules, which self-organize into multi-unit, millimeter-size assemblies under rotating magnetic fields. These microcapsules exhibit high peroxidase-like activity, efficiently catalyzing hydrogen peroxide to generate reactive oxygen species (ROS). Notably, microcapsule assemblies display remarkable collective navigation within arched and branched confinements, reaching the targeted apical regions of the tooth canal with high accuracy. Furthermore, these nanozyme-shelled microrobots perform rapid catalysis in situ and effectively kill biofilms on contact via ROS generation, enabling localized antibiofilm action. This study demonstrates a facile method of integrating nanozymes onto a versatile microrobotic platform to address current needs for targeted therapeutic catalysis in complex and confined microenvironments.

Objectives Evaluate the reproducibility, temperature sensitivity, and radiation dose requirements of spectral CT thermometry in tissue-mimicking phantoms to establish its utility for non-invasive temperature monitoring of thermal ablations. Materials and Methods Three liver mimicking phantoms embedded with temperature sensors were individually scanned with a dual-layer spectral CT at different radiation dose levels during heating and cooling (35 to 80 °C). Physical density maps were reconstructed from spectral results using a range of reconstruction parameters. Thermal volumetric expansion was then measured at each temperature sensor every 5°C in order to establish a correlation between physical density and temperature. Linear regressions were applied based on thermal volumetric expansion for each phantom, and coefficient of variation for fit parameters was calculated to characterize reproducibility of spectral CT thermometry. Additionally, temperature sensitivity was determined to evaluate the effect of acquisition parameters, reconstruction parameters, and image denoising. The resulting minimum radiation dose to meet the clinical temperature sensitivity requirement was determined for each slice thickness, both with and without additional denoising. Results Thermal volumetric expansion was robustly replicated in all three phantoms, with a correlation coefficient variation of only 0.43%. Similarly, the coefficient of variation for the slope and intercept were 9.6% and 0.08%, respectively, indicating reproducibility of the spectral CT thermometry. Temperature sensitivity ranged from 2 to 23 °C, decreasing with increased radiation dose, slice thickness, and iterative reconstruction level. To meet the clinical requirement for temperature sensitivity, the minimum required radiation dose ranged from 20, 30, and 57 mGy for slice thickness of 2, 3, and 5 mm, respectively, but was reduced to 2 mGy with additional denoising. Conclusions Spectral CT thermometry demonstrated reproducibility across three liver-mimicking phantoms and illustrated the clinical requirement for temperature sensitivity can be met for different slice thicknesses. Moreover, additional denoising enables the use of more clinically relevant radiation doses, facilitating the clinical translation of spectral CT thermometry. The reproducibility and temperature accuracy of spectral CT thermometry enable its clinical application for non-invasive temperature monitoring of thermal ablation.

Complex metal nanostructures represent an exceptional category of materials characterized by distinct morphologies and physicochemical properties. Nanostructures with shape anisotropies, such as nanorods, nanostars, nanocages, and nanoprisms, are particularly appealing due to their tunable surface plasmon resonances, controllable surface chemistries, and effective targeting capabilities. These complex nanostructures can absorb light in the near-infrared, enabling noteworthy applications in nanomedicine, molecular imaging, and biology. The engineering of targeting abilities through surface modifications involving ligands, antibodies, peptides, and other agents potentiates their effects. Recent years have witnessed the development of innovative structures with diverse compositions, expanding their applications in biomedicine. These applications encompass targeted imaging, surface-enhanced Raman spectroscopy, near-infrared II imaging, catalytic therapy, photothermal therapy, and cancer treatment. This review seeks to provide the nanomedicine community with a thorough and informative overview of the evolving landscape of complex metal nanoparticle research, with a specific emphasis on their roles in imaging, cancer therapy, infectious diseases, and biofilm treatment. This article is categorized under: Diagnostic Tools > In Vivo Nanodiagnostics and Imaging Therapeutic Approaches and Drug Discovery > Nanomedicine for Infectious Disease Diagnostic Tools > Diagnostic Nanodevices.

Photon-counting mammography is an emerging modality that allows for spectral imaging and provides a differentiation of material compositions. The development of photon-counting mammography-specific contrast agents has yet to be explored. In this study, the contrast, sensitivity, and organ dose between silver sulfide nanoparticles (Ag2S-NPs) and a clinically approved iodinated agent (iopamidol) were investigated using a contrast-embedded gradient ramp phantom and a prototype scanner. For a given agent, the signal intensity increased with concentration, tube voltage (kV), and high bin fraction, while remaining constant with the tube current exposure time product (mAs). Moreover, Ag2S-NPs produced significantly stronger contrast and improved sensitivity compared to iodine, especially when imaged at lower tube energies. Therefore, the use of photon-counting techniques and a silver-based contrast agent may markedly increase the contrast and contrast-to-noise ratios or reduce the radiation dose for contrast-enhanced mammography. Silver may be better suited than iodine for contrast agent development for spectral photon-counting mammography.

Immunotherapies have become the standard treatment for melanoma. To further improve patient responses, combinations of immunotherapies and radiotherapy (RT) are being studied, since radiotherapies can potentially provide additional immune stimulation, in addition to direct antitumor effects. FLASH-RT is a novel, ultrahigh dose rate, radiation delivery approach, with the potential of at least equivalent tumor control efficacy and reduced damage to healthy tissue. However, the effects of combining FLASH-RT and immunotherapy have not been extensively studied in melanoma. Toll-like receptor (TLR) agonists, such as imiquimod (IMQ), are potent immunostimulatory agents, although their utility is limited due to poor solubility and systemic side effects. We therefore developed a novel combination therapy for melanoma consisting of IMQ delivered to the tumor via a radiopaque and radiation responsive hydrogel combined with FLASH-RT. We found that FLASH was able to effectively stimulate IMQ release from the hydrogel. In addition, we found that the combination of FLASH and released IMQ resulted in synergistic melanoma cell killing in vitro. The combination therapy reduced tumor growth compared to controls, enhanced survival, and resulted in remarkable enhancements in certain tumor cytokine levels. CT imaging allowed the hydrogel to be monitored in vivo. In addition, no adverse effects of the treatment were observed. Overall, this IMQ-gel and FLASH-RT combination may have potential as an improved treatment for melanoma and indicates that the interactions of FLASH-RT and TLR agonists merit further study.

Dental caries is the most common human disease caused by oral biofilms despite the widespread use of fluoride as the primary anticaries agent. Recently, an FDA-approved iron oxide nanoparticle (ferumoxytol, Fer) has shown to kill and degrade caries-causing biofilms through catalytic activation of hydrogen peroxide. However, Fer cannot interfere with enamel acid demineralization. Here, we show notable synergy when Fer is combined with stannous fluoride (SnF 2 ), markedly inhibiting both biofilm accumulation and enamel damage more effectively than either alone. Unexpectedly, we discover that the stability of SnF 2 is enhanced when mixed with Fer in aqueous solutions while increasing catalytic activity of Fer without any additives. Notably, Fer in combination with SnF 2 is exceptionally effective in controlling dental caries in vivo, even at four times lower concentrations, without adverse effects on host tissues or oral microbiome. Our results reveal a potent therapeutic synergism using approved agents while providing facile SnF 2 stabilization, to prevent a widespread oral disease with reduced fluoride exposure.