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The use of nanoparticles in the biomedical field has gained much attention due to their applications in biomedical imaging, drug delivery, and therapeutics. Silver telluride nanoparticles (Ag

Significant work has been done to develop nanoparticle contrast agents for computed tomography (CT), with a focus on identifying safer and more effective formulations. Contrast agents for spectral photon-counting computed tomography (SPCCT), a fast-growing imaging modality derived from conventional CT, have also recently gained considerable attention. In this study, we explored the synthesis of ultrasmall ytterbium nanoparticles (YbNP) and demonstrated that, potentially, they can be used as conventional CT and SPCCT contrast agents. These nanoparticles were tested

Biofilms are structured communities of microbial cells embedded in a self-produced matrix of extracellular polymeric substances. Biofilms are associated with many health issues in humans, including chronic wound infections and tooth decay. Current antimicrobials are often incapable of disrupting the polymeric biofilm matrix and reaching the bacteria within. Alternative approaches are needed. Here, we describe a unique structure of dextran coated gold in a gold cage nanoparticle that enables photoacoustic and photothermal properties for biofilm detection and treatment. Activation of these nanoparticles with a near infrared laser can selectively detect and kill biofilm bacteria with precise spatial control and in a short timeframe. We observe a strong biocidal effect against both Streptococcus mutans and Staphylococcus aureus biofilms in mouse models of oral plaque and wound infections respectively. These effects were over 100 times greater than that seen with chlorhexidine, a conventional antimicrobial agent. Moreover, this approach did not adversely affect surrounding tissues. We conclude that photothermal ablation using theranostic nanoparticles is a rapid, precise, and non-toxic method to detect and treat biofilm-associated infections.

International audience; The activation of phagocytic cells is a hallmark of many neurological diseases. Imaging them in their 3-dimensional cerebral environment over time is crucial to better understand their role in disease pathogenesis and to monitor their potential therapeutic effects. Phagocytic cells have the ability to internalize metal-based contrast agents both in vitro and in vivo and can thus be tracked by magnetic resonance imaging (MRI) or computed tomography (CT). In this review article, we summarize the different labelling strategies, contrast agents, and in vivo imaging modalities that can be used to monitor cells with phagocytic activity in the central nervous system using MRI and CT, with a focus on clinical applications. Metal-based nanoparticle contrast agents such as gadolinium, gold and iron are ideal candidates for these applications as they have favourable magnetic and/or radiopaque properties and can be fine-tuned for optimal uptake by phagocytic cells. However, they also come with downsides due to their potential toxicity, especially in the brain where they might accumulate. We therefore conclude our review by discussing the pitfalls, safety and potential for clinical translation of these metal-based neuroimaging techniques. Early results in patients with neuropathologies such as multiple sclerosis, stroke, trauma, cerebral aneurysm and glioblastoma are promising. If the challenges represented by safety issues are overcome, phagocytic cells imaging will be a very valuable tool for studying and understanding the inflammatory response and evaluating treatments that aim at mitigating this response in patients with neurological diseases.

Most current nanoparticle formulations have relatively low clearance efficiency, which may hamper their likelihood for clinical translation. Herein, we sought to compare the clearance and cellular distribution profiles between sub-5 nm, renally-excretable silver sulfide nanoparticles (Ag(2)S-NPs) synthesized via either a bulk, high temperature, or a microfluidic, room temperature approach. We found that the thermolysis approach led to significant ligand degradation, but the surface coating shell was unaffected by the microfluidic synthesis. We demonstrated that the clearance was improved for Ag(2)S-NPs with intact ligands, with less uptake in the liver. Moreover, differential distribution in hepatic cells was observed, where Ag(2)S-NPs with degraded coatings tend to accumulate in Kupffer cells and those with intact coatings are more frequently found in hepatocytes. Therefore, understanding the impact of synthetic processes on ligand integrity and subsequent nano-biointeractions will aid in designing nanoparticle platforms with enhanced clearance and desired distribution profiles.

Severe tooth decay has been associated with iron deficiency anemia that disproportionally burdens susceptible populations. Current modalities are insufficient in severe cases where pathogenic dental biofilms rapidly accumulate, requiring new antibiofilm approaches. Here, we show that ferumoxytol, a Food and Drug Administration-approved nanoparticle formulation for treating iron deficiency, exerts an alternative therapeutic activity via the catalytic activation of hydrogen peroxide, which targets bacterial pathogens in biofilms and suppresses tooth enamel decay in an intraoral human disease model. Data reveal the potent antimicrobial specificity of ferumoxytol iron oxide nanoparticles (FerIONP) against biofilms harboring Streptococcus mutans via preferential binding that promotes bacterial killing through in situ free-radical generation. Further analysis indicates that the targeting mechanism involves interactions of FerIONP with pathogen-specific glucan-binding proteins, which have a minimal effect on commensal streptococci. In addition, we demonstrate that FerIONP can detect pathogenic biofilms on natural teeth via a facile colorimetric reaction. Our findings provide clinical evidence and the theranostic potential of catalytic nanoparticles as a targeted anti-infective nanomedicine.

Silver sulfide nanoparticles (Ag2S NPs) have gained considerable interest in the biomedical field due to their photothermal ablation enhancement, near-infrared fluorescence properties, low toxicity levels, and multi-imaging capabilities. Silver telluride nanoparticles (Ag2Te NPs) have similar properties to Ag2S NPs, should also be stable due to an extremely low solubility product and should generate greater X-ray contrast since tellurium is significantly more attenuating than sulfur at diagnostic X-ray energies. Despite these attractive properties, Ag2Te NPs have only been studied in vivo once and at a low dose (2 mg Ag per kg). Herein, for the first time, Ag2Te NPs' properties and their application in the biomedical field were studied in vivo in the setting requiring the highest nanoparticle doses of all biomedical applications, i.e. X-ray imaging. Ag2Te NPs were shown to be stable, biocompatible (no acute toxicity observed in the cell lines studied or in vivo), and generated higher contrast, compared to controls, in the two X-ray imaging techniques studied: computed tomography (CT) and dual-energy mammography (DEM). In summary, this is the first study where Ag2Te NPs were explored in vivo at a high dose. Our findings suggest that Ag2Te NPs provide strong X-ray contrast while exhibiting excellent biocompatibility. These results highlight the potential use of Ag2Te NPs in the biomedical field and as X-ray contrast agents for breast cancer screening.

Silver chalcogenide (Ag(2)X, where X = S, Se, or Te) nanoparticles have been extensively investigated for their applications in electronics but have only recently been explored for biomedical applications. In the past 10 years, Ag(2)X, primarily silver sulfides at first, have become of great importance as quantum dots, since they not only possess excellent deep tissue imaging properties in the near-infrared regions I and II, but also have low toxicities. Their appealing properties have led to numerous recent developments of Ag(2)X for biomedical applications. Furthermore, Ag(2)X have been discovered in the past 2–3 years to be potent X-ray contrast agents, adding to the numerous biomedical uses of these nanoparticles. In this review, we discuss the most recent advances in silver chalcogenide nanoparticle use in areas such as bioimaging, theranostics, and biosensors. Moreover, we examine the advances in synthetic approaches for these nanoparticles, which include aqueous and organic syntheses routes. Finally, we discuss the advantages and current limitations in the use of silver chalcogenides for different biomedical applications and their potential for advancement and expansions in use.

Gold nanoparticles (AuNP) are well-established contrast agents in computed tomography (CT) and photoacoustic imaging (PAI). A wide variety of AuNP sizes, shapes, and coatings have been reported for these applications. However, for clinical translation, AuNP should be excretable to avoid long-term accumulation and possible side effects. Sub-5 nm AuNP have the benefit to be excretable through kidney filtration, therefore their loading in biodegradable nanogels holds promise to result in contrast agents that have long circulation times in the vasculature and subsequent biodegradation for excretion. Polyphosphazenes are intrinsically biodegradable polymers capable of forming nanogels with high payloads, and to release their payloads upon degradation. The significant development in polyphosphazenes that have tailored degradation kinetics, and their formulation with drugs or contrast agents, has shown potential as a biodegradable platform for imaging vasculature and endogenous molecules, by combination of CT and PA modalities. Therefore, we herein present methods for the formulation of AuNP assemblies loaded in nanogels composed of biodegradable polyphosphazenes, with a size range from 50 to 200 nm. We describe protocols for their characterization by UV-vis spectroscopy, Fourier-transform infrared spectroscopy, various microscopy techniques, elemental quantification by induced coupling plasma optical emission spectroscopy and contrast production in both CT and PAI. Finally, we detail the methods to investigate their effect on cells, distribution in cells and imaging properties for detection of endogenous molecules.

Gold nanoparticles (AuNP) are well-established contrast agents in computed tomography (CT) and photoacoustic imaging (PAI). A wide variety of AuNP sizes, shapes, and coatings have been reported for these applications. However, for clinical translation, AuNP should be excretable to avoid long-term accumulation and possible side effects. Sub-5 nm AuNP have the benefit to be excretable through kidney filtration, therefore their loading in biodegradable nanogels holds promise to result in contrast agents that have long circulation times in the vasculature and subsequent biodegradation for excretion. Polyphosphazenes are intrinsically biodegradable polymers capable of forming nanogels with high payloads, and to release their payloads upon degradation. The significant development in polyphosphazenes that have tailored degradation kinetics, and their formulation with drugs or contrast agents, has shown potential as a biodegradable platform for imaging vasculature and endogenous molecules, by combination of CT and PA modalities. Therefore, we herein present methods for the formulation of AuNP assemblies loaded in nanogels composed of biodegradable polyphosphazenes, with a size range from 50 to 200 nm. We describe protocols for their characterization by UV-vis spectroscopy, Fourier-transform infrared spectroscopy, various microscopy techniques, elemental quantification by induced coupling plasma optical emission spectroscopy and contrast production in both CT and PAI. Finally, we detail the methods to investigate their effect on cells, distribution in cells and imaging properties for detection of endogenous molecules.

Ferumoxytol is an intravenous iron oxide nanoparticle formulation that has been approved by the U.S. Food and Drug Administration (FDA) for treating anemia in patients with chronic kidney disease. In recent years, ferumoxytol has also been demonstrated to have potential for many additional biomedical applications due to its excellent inherent physical properties, such as superparamagnetism, biocatalytic activity, and immunomodulatory behavior. With good safety and clearance profiles, ferumoxytol has been extensively utilized in both preclinical and clinical studies. Here, we first introduce the medical needs and the value of current iron oxide nanoparticle formulations in the market. We then focus on ferumoxytol nanoparticles and their physicochemical, diagnostic, and therapeutic properties. We include examples describing their use in various biomedical applications, including magnetic resonance imaging (MRI), multimodality imaging, iron deficiency treatment, immunotherapy, microbial biofilm treatment and drug delivery. Finally, we provide a brief conclusion and offer our perspectives on the current limitations and emerging applications of ferumoxytol in biomedicine. Overall, this review provides a comprehensive summary of the developments of ferumoxytol as an agent with diagnostic, therapeutic, and theranostic functionalities.

Numerous formulations of nanoparticle-based X-ray computed tomography (CT) contrast agents made of heavy metal elements are under investigation for their ability to provide improved CT imaging. Thus far, most experimental nanoparticle-based CT contrast agents have been developed with atoms of a single element. However, inspired by the composites formed from multiple elements used in radioprotective garments, we hypothesized that contrast agents made of several elements whose K-edge energies are spaced out in the high photon flux region could achieve high, broadband X-ray attenuation across the energies used in X-ray source spectra. Herein, we synthesized sub-5 nm core inorganic nanoparticles containing gold, tantalum, and cerium, and encapsulated them in polymeric nanoparticles to form polymetal nanoparticles (PMNP). We found that PMNP with multiple payload elements generate higher and more stable CT contrast than contrast agents made from a single contrast generating material, demonstrating the potential benefits of incorporating multiple suitable elements as CT contrast payloads.

Significant effort has been focused on developing renally-clearable nanoparticle agents since efficient renal clearance is important for eventual clinical translation. Silver sulfide nanoparticles (Ag(2)S-NP) have recently been identified as contrast agents for dual energy mammography, computed tomography (CT) and fluorescence imaging and probes for drug delivery and photothermal therapy with good biocompatibility. However, most Ag(2)S-NP reported to date are not renally excretable and are observed in vivo to accumulate and remain in the reticuloendothelial system (RES) organs, i.e. liver and spleen, for a long time, which could negatively impact their likelihood for translation. Herein, we present renally-clearable, 3.1 nm Ag(2)S-NP with 85% of the injected dose (ID) being excreted within 24 hours of intravenous injection, which is amongst the best clearance of similarly sized nanoparticles reported thus far (mostly between 20-75% of ID). The urinary excretion and low RES accumulation of these nanoparticles in mice were indicated by in vivo CT imaging and biodistribution analysis. In summary, these ultrasmall Ag(2)S-NP can be effectively eliminated via urine and have high translational potential for various biomedical applications.

Successful treatment of glioblastoma (GBM) is hampered by primary tumor recurrence after surgical resection and poor prognosis, despite adjuvant radiotherapy and chemotherapy. In search of improved outcomes for this disease, quisinostat appeared as a lead compound in drug screening. A delivery system was devised for this drug and to exploit current clinical methodology: an injectable hydrogel, loaded with both the quisinostat drug and radiopaque gold nanoparticles (AuNP) as contrast agent, that can release these payloads as a response to radiation. This hydrogel grants high local drug concentrations, overcoming issues with current standards of care. Significant hydrogel degradation and quisinostat release were observed due to the radiation trigger, providing high in vitro anticancer activity. In vivo, the combination of radiotherapy and the radiation-induced delivery of quisinostat from the hydrogel, successfully inhibited tumor growth in a mice model bearing xenografted human GBM tumors with a total response rate of 67%. Long-term tolerability was observed after intratumoral injection of the quisinostat loaded hydrogel. The AuNP payload enabled precise image-guided radiation delivery and the monitoring of hydrogel degradation using computed tomography (CT). These exciting results highlight this hydrogel as a versatile imageable drug delivery platform that can be activated simultaneously to radiation therapy and potentially offers improved treatment for GBM.

Background Macrophage burden is a major factor in the risk of atherosclerotic plaque rupture, and its evaluation remains challenging with molecular noninvasive imaging approaches. Photon-counting CT (PCCT) with k-edge imaging aims to allow for the specific detection of macrophages using gold nanoparticles. Purpose To perform k-edge imaging in combination with gold nanoparticles to detect and quantify the macrophage burden within the atherosclerotic aortas of rabbits. Materials and Methods Atherosclerotic and control New Zealand white rabbits were imaged before and at several time points up to 2 days after intravenous injection of gold nanoparticles (3.5 mL/kg, 65 mg gold per milliliter). Aortic CT angiography was performed at the end of the follow-up using an intravenous injection of an iodinated contrast material. Gold k-edge and conventional CT images were reconstructed for qualitative and quantitative assessment of the macrophage burden. PCCT imaging results were compared with findings at histologic examination, quantitative histomorphometry, transmission electron microscopy, and quantitative inductively coupled plasma optical emission spectrometry. Pearson correlations between the macrophage area measured in immunostained sections and the concentration of gold and attenuation measured in the corresponding PCCT sections were calculated. Results Seven rabbits with atherosclerosis and four control rabbits without atherosclerosis were analyzed. In atherosclerotic rabbits, calcifications were observed along the aortic wall before injection. At 2 days after injection of gold nanoparticles, only gold k-edge images allowed for the distinction of plaque enhancement within calcifications and for lumen enhancement during angiography. A good correlation was observed between the gold concentration measured within the wall and the macrophage area in 35 plaques (five per rabbit) (

Cerium oxide nanoparticles (CeONP), having potent antioxidant properties, are highly promising nanomaterials for treatment of diseases in which oxidative stress from excessive reactive oxygen species (ROS) plays a critical role in the pathogenesis and progression. However, most previously reported CeONP formulations were not efficiently cleared from the body, precluding their clinical translation. Herein, we report ultrasmall CeONP that can mitigate activation of macrophages and subsequent acute inflammation. It is found that these CeONP can effectively scavenge reactive species, inhibit macrophage activation, and minimize their recruitment and infiltration to the inflammation site, which lead to alleviation of edema and pain hypersensitivity. Moreover, we demonstrate that CeONP can be effectively excreted from the body within 24 h of systemic administration, minimizing long-term toxicity concerns. Altogether, our findings suggest that CeONP may be explored as both antioxidant and anti-inflammatory agents that can reduce acute inflammation with a better safety profile than existing nanoparticles.

Silver sulfide nanoparticles (Ag(2)S NPs) have gained considerable interest in the biomedical field due to their photothermal ablation enhancement, near-infrared fluorescence properties, low toxicity levels, and multi-imaging capabilities. Silver telluride nanoparticles (Ag(2)Te NPs) have similar properties to Ag(2)S NPs, should also be stable due to an extremely low solubility product and should generate greater X-ray contrast since tellurium is significantly more attenuating than sulfur at diagnostic X-ray energies. Despite these attractive properties, Ag(2)Te NPs have only been studied in vivo once and at a low dose (2 mg Ag per kg). Herein, for the first time, Ag(2)Te NPs’ properties and their application in the biomedical field were studied in vivo in the setting requiring the highest nanoparticle doses of all biomedical applications, i.e. X-ray imaging. Ag(2)Te NPs were shown to be stable, biocompatible (no acute toxicity observed in the cell lines studied or in vivo), and generated higher contrast, compared to controls, in the two X-ray imaging techniques studied: computed tomography (CT) and dual-energy mammography (DEM). In summary, this is the first study where Ag(2)Te NPs were explored in vivo at a high dose. Our findings suggest that Ag(2)Te NPs provide strong X-ray contrast while exhibiting excellent biocompatibility. These results highlight the potential use of Ag(2)Te NPs in the biomedical field and as X-ray contrast agents for breast cancer screening.

Computed tomography (CT) is an x-ray based medical imaging technique commonly used for non-invasive gastrointestinal tract (GIT) imaging. Iodine and barium based CT contrast agents are used in the clinic for GIT imaging, however, inflammatory bowel disease (IBD) imaging is challenging since iodinated and barium based CT agents are not specific for sites of inflammation. Cerium oxide nanoparticles (CeNP) can produce strong x-ray attenuation due to cerium’s k-edge at 40.4 keV, but have not yet been explored for CT imaging. In addition, we hypothesized that the use of dextran as a coating material on cerium oxide nanoparticles would encourage accumulation in IBD inflammation sites in a similar fashion to other inflammatory diseases. In this study, therefore, we sought to develop a CT contrast agent, i.e. dextran coated cerium oxide nanoparticles (Dex-CeNP) for GIT imaging with IBD. We synthesized Dex-CeNP, characterized them using various analytical tools and examined their in vitro biocompatibility, CT contrast generation and protective effect against oxidative stress. In vivo CT imaging was done with both healthy mice and a dextran sodium sulfate induced colitis (DSS-colitis) mouse model. Dex-CeNP’s CT contrast generation and accumulation in inflammation sites were compared with iopamidol, an FDA approved CT contrast agent. Dex-CeNP was found to be protective against oxidative damage. Dex-CeNP produced strong CT contrast and accumulated in the colitis area of large intestines. In addition, >97 % of oral doses were cleared from the body within 24 hrs. Therefore, Dex-CeNP can be used as a potential CT contrast agent for imaging GIT with IBD, while protecting against oxidative damage.

Human dental caries is an intractable biofilm-associated disease caused by microbial interactions and dietary sugars on the host’s teeth. Commensal bacteria help control opportunistic pathogens via bioactive products such as hydrogen peroxide (H(2)O(2)). However, high-sugar consumption disrupts homeostasis and promotes pathogen accumulation in acidic biofilms that cause tooth-decay. Here, we exploit the pathological (sugar-rich/acidic) conditions using a nanohybrid system to increase intrinsic H(2)O(2) production and trigger pH-dependent reactive oxygen species (ROS) generation for efficient biofilm virulence targeting. The nanohybrid contains glucose-oxidase that catalyzes glucose present in biofilms to increase intrinsic H(2)O(2), which is converted by iron oxide nanoparticles with peroxidase-like activity into ROS in acidic pH. Notably, it selectively kills Streptococcus mutans (pathogen) without affecting Streptococcus oralis (commensal) via preferential pathogen-binding and in situ ROS generation. Furthermore, nanohybrid treatments potently reduced dental caries in a rodent model. Compared to chlorhexidine (positive-control), which disrupted oral microbiota diversity, the nanohybrid had significant higher efficacy without affecting soft-tissues and the oral-gastrointestinal microbiomes, while modulating dental health-associated microbial activity in vivo. The data reveal therapeutic precision of a bi-functional hybrid nanozyme against a biofilm-related disease in a controlled-manner activated by pathological conditions.

X-ray imaging is the most widely used diagnostic imaging method in modern medicine and several advanced forms of this technology have recently emerged. Iodinated molecules and barium sulfate suspensions are clinically approved X-ray contrast agents and are widely used. However, these existing contrast agents provide limited information, are suboptimal for new X-ray imaging techniques and are developing safety concerns. Thus, over the past 15 years, there has been a rapid growth in the development of nanoparticles as X-ray contrast agents. Nanoparticles have several desirable features such as high contrast payloads, the potential for long circulation times, and tunable physicochemical properties. Nanoparticles have also been used in a range of biomedical applications such as disease treatment, targeted imaging, and cell tracking. In this review, we discuss the principles behind X-ray contrast generation and introduce new types of X-ray imaging modalities, as well as potential elements and chemical compositions that are suitable for novel contrast agent development. We focus on the progress in nanoparticle X-ray contrast agents developed to be renally clearable, long circulating, theranostic, targeted, or for cell tracking. We feature agents that are used in conjunction with the newly developed multi-energy computed tomography and mammographic imaging technologies. Finally, we offer perspectives on current limitations and emerging research topics as well as expectations for the future development of the field. This article is categorized under: Diagnostic Tools > in vivo Nanodiagnostics and Imaging Nanotechnology Approaches to Biology > Nanoscale Systems in Biology.

Biofilms are surface-attached bacterial communities embedded within an extracellular matrix that create localized and protected microenvironments. Acidogenic oral biofilms can demineralize the enamel-apatite on teeth, causing dental caries (tooth decay). Current antimicrobials have low efficacy and do not target the protective matrix and acidic pH within the biofilm. Recently, catalytic nanoparticles were shown to disrupt biofilms but lacked a stabilizing coating required for clinical applications. Here, we report dextran-coated iron oxide nanoparticles termed nanozymes (Dex-NZM) that display strong catalytic (peroxidase-like) activity at acidic pH values, target biofilms with high specificity, and prevent severe caries without impacting surrounding oral tissues in vivo. Nanoparticle formulations were synthesized with dextran coatings (molecular weights from 1.5 to 40 kDa were used), and their catalytic performance and bioactivity were assessed. We found that 10 kDa dextran coating provided maximal catalytic activity, biofilm uptake, and antibiofilm properties. Mechanistic studies indicated that iron oxide cores are the source of catalytic activity, whereas dextran on the nanoparticle surface provided stability without blocking catalysis. Dextran-coating facilitated NZM incorporation into exopolysaccharides (EPS) structure and binding within biofilms, which activated hydrogen peroxide (H(2)O(2)) for localized bacterial killing and EPS-matrix breakdown. Surprisingly, dextran coating enhanced selectivity toward biofilms while avoiding binding to gingival cells. Furthermore, Dex-NZM/H(2)O(2) treatment significantly reduced the onset and severity of caries lesions (vs control or either Dex-NZM or H(2)O(2) alone) without adverse effects on gingival tissues or oral microbiota diversity in vivo. Therefore, dextran-coated nanozymes have potential as an alternative treatment to control tooth decay and possibly other biofilm-associated diseases.

Gold is a highly useful nanomaterial for many clinical applications, but its poor biodegradability can impair long-term physiological clearance. Large gold nanoparticles (20–200 nm), such as those required for long blood circulation times and appreciable tumor localization, often exhibit little to no dissolution and excretion. This can be improved by incorporating small gold particles within a larger entity, but elimination may still be protracted due to incomplete dispersion of gold. The present study describes a novel gold nanoparticle formulation capable of environmentally-triggered decomposition. Ultrasmall gold nanoparticles are coated with thiolated dextran, and hydrophobic acetal groups are installed through direct covalent modification of the dextran. This hydrophobic exterior allows gold to be densely packed within ~150-nm polymeric micelles. Upon exposure to an acidic environment, the acetal groups are cleaved and the gold nanoparticles become highly water-soluble, leading to destabilization of the micelle. Within 24 hours, the ultrasmall water-soluble gold particles are released from the micelle and readily dispersed. Micelle degradation and gold nanoparticle dispersion was imaged in cultured macrophages, and micelle-treated mice displayed progressive physiological clearance of gold, with > 85% elimination from the liver over three months. These particles present a novel nanomaterial formulation and address a critical unresolved barrier for clinical translation of gold nanoparticles.

Nonsteroidal anti-inflammatory drugs (NSAIDs) relieve inflammatory pain by predominant suppression of cyclooxygenase-2 derived prostaglandin (PG) E2. Innate immune cells contribute to inflammatory pain hypersensitivity and may be an attractive target for novel non-addictive approaches to pain management. We studied the contribution of PGE2 produced by myeloid cell microsomal prostaglandin E synthase -1 (mPGES-1) to peripheral inflammation and hyperalgesia in mice. Selective deletion of mPGES-1 in myeloid cells by crossing LysM-Cre mice with mPGES-1flox/flox mice (Mac-mPGES-1-KO) resulted in significantly reduced mechanical and thermal hyperalgesia in complete Freund’s adjuvant (CFA)-evoked hind paw inflammation, zymosan-induced peri-articular inflammation and collagen II antibody-induced arthritis models. Systemic COX-2 inhibition or myeloid cell specific COX-2 deletion (by crossing LysM-Cre with COX-2 flox/flox mice) recapitulated reduction of CFA-induced inflammation and hyperalgesia. In contrast, deletion of mPGES-1 in neurons and glial cells by crossing mPGES-1flox/flox mice with Nestin-Cre mice had no detectable effect on inflammatory pain hypersensitivity. While macrophage recruitment was unaltered, tissue concentrations of PGE2, IL-1β and TNFα were significantly reduced in Mac-mPGES-1-KO paw tissues following CFA induction. Our results demonstrate that myeloid cell mPGES-1 is the dominant source of PGE2 in inflammatory pain hypersensitivity. Targeting myeloid cell mPGES-1 may afford a novel approach to inflammatory pain therapy.

Two bismuth–organic network polymers were synthesized by means of a one-step polycondensation reaction between an aromatic dithiol/trithiol and triphenylbismuth. The materials were characterized by solid-state UV–vis spectroscopy, Raman spectroscopy, scanning electron microscopy, energy dispersive X-ray spectroscopy, powder X-ray diffraction, elemental microanalysis, and thermogravimetric analysis. Uniform dispersion of the hydrophobic and water-insoluble bismuth-containing polymers in aqueous media was achieved by the addition of 2 kDa poly(ethylene glycol) methyl ether thiol. This enabled quantitative phantom imaging experiments on a clinical computed tomography (CT) scanner, which showed that the coordination polymers possessed strong CT contrast properties. The observed X-ray attenuation properties of each coordination polymer were correlated with its bismuth payload. The X-ray opacity, thermal and chemical stabilities, and aqueous dispersibility of this novel class of bismuth–organic materials make them potentially useful as biomedical CT contrast agents and radiopaque materials.

Conventional X-ray mammography has low diagnostic sensitivity for women with dense breasts. As a result, alternative contrast-enhanced screening tools such as dual energy mammography (DEM), computed tomography (CT), magnetic resonance imaging (MRI), and near-infrared fluorescence (NIRF) imaging are being used or investigated for these women. However, currently available contrast agents are non-ideal, have safety issues, and each imaging technique requires a different contrast agent. We therefore sought to develop a multimodal contrast agent that is functional for each breast imaging modality to simplify the diagnosis process and address the issues of existing contrast agents. Herein, we present a novel “all-in-one” nanoparticle (AION) multimodal imaging probe that has potent DEM, CT, MRI, and NIRF contrast properties and improved biocompatibility. AION were formed by co-encapsulation of a near-infrared fluorophore (DiR), silver sulfide nanoparticles (Ag(2)S-NP), and iron oxide nanoparticles (IO-NP) in PEGylated micelles. AION showed negligible cytotoxicity, which was in agreement with its minimal silver ion release profiles. AION generated strong contrast with all imaging modalities as demonstrated in phantom imaging. AION allowed in vivo tumor imaging as evidenced by the increase in contrast after injection. This study indicates the potential of AION as an effective multimodal contrast agent for breast cancer diagnosis with a range of imaging methods.

Spectral photon-counting CT (SPCCT) is an emerging X-ray imaging technology that extends the scope of available diagnostic imaging tools. The main advantage of photon-counting CT technology is better sampling of the spectral information from the transmitted spectrum in order to benefit from additional physical information being produced during matter interaction, including photo-electric and Compton effects, and the K-edge effect. The K-edge, which is specific for a given element, is the increase in X-ray absorption of the element above the binding energy between its inner electronic shell and the nucleus. Hence, the spectral information contributes to better characterization of tissues and materials of interest, explaining the excitement surrounding this area of X-ray imaging. Other improvements of SPCCT compared with conventional CT, such as higher spatial resolution, lower radiation exposure and lower noise are also expected to provide benefits for diagnostic imaging. In this review, we describe multi-energy CT imaging, from dual energy to photon counting technology, and our initial experience results using a clinical-scale spectral photon counting CT (SPCCT) prototype system in vitro and in vivo. In addition, possible clinical applications are introduced.

Efforts to develop novel cell-based therapies originated with the first bone marrow transplant on a leukemia patient in 1956. Preclinical and clinical examples of cell-based treatment strategies have shown promising results across many disciplines in medicine, with recent advances in immune cell therapies for cancer producing remarkable response rates, even in patients with multiple treatment failures. However, cell-based therapies suffer from inconsistent outcomes, motivating the search for tools that allow monitoring of cell delivery and behavior in vivo. Noninvasive cell imaging techniques, also known as cell tracking, have been developed to address this issue. These tools can allow real-time, quantitative, and long-term monitoring of transplanted cells in the recipient, providing insight on cell migration, distribution, viability, differentiation, and fate, all of which play crucial roles in treatment efficacy. Understanding these parameters allows the optimization of cell choice, delivery route, and dosage for therapy and advances cell-based therapy for specific clinical uses. To date, most cell tracking work has centered on imaging modalities such as MRI, radionuclide imaging, and optical imaging. However, X-ray computed tomography (CT) is an emerging method for cell tracking that has several strengths such as high spatial and temporal resolution, and excellent quantitative capabilities. The advantages of CT for cell tracking are enhanced by its wide availability and cost effectiveness, allowing CT to become one of the most popular clinical imaging modalities and a key asset in disease diagnosis. In this review, we will discuss recent advances in cell tracking methods using X-ray CT in various applications, in addition to predictions on how the field will progress.

Designing personalized cancer nanomedicines is a challenging process. The emerging field of nanoinformatics can facilitate this process by enabling computational design of nanocarrier-encapsulated drugs. Recent data show that quantitative structure–nanoparticle assembly calculations predict particle formation and size, and can lead to safer and more effective personalized cancer therapeutics.

Gold nanoparticles (AuNP) have been extensively developed as contrast agents, theranostic platforms and probes for molecular imaging. This popularity has yielded a large number of AuNP designs that vary in size, shape, surface functionalization and assembly, to match very closely to the requirements for various imaging applications. Hence, AuNP based probes for molecular imaging allow the use of computed tomography (CT), fluorescence and other forms of optical imaging, photoacoustic imaging (PAI) and magnetic resonance imaging (MRI), and other newer techniques. The unique physico-chemical properties, biocompatibility and highly developed chemistry of AuNP have facilitated breakthroughs in molecular imaging that allow the detection and imaging of physiological processes with a high sensitivity and spatial resolution. In this review, we summarize the recent advances in molecular imaging achieved using novel AuNP structures, cell tracking using AuNP, targeted AuNP for cancer imaging, and activatable AuNP probes. Finally, the perspectives and current limitations for the clinical translation of AuNP based probes are discussed.

The objective of our study was to evaluate the feasibility of using silver sulfide nanoparticles (Ag2S-NP) as a contrast agent for photon-counting mammography. The efficacies of Ag2S-NP and iodine contrast were evaluated using a contrastembedded gradient phantom. The phantom was constructed using tissue-equivalent materials and varied continuously in composition from 100% glandular tissue to 100% adipose tissue. Each contrast agent was prepared at eight different concentrations: 1, 2, 5, 10, 15, 20, 25, and 30 mg/mL. Tubes of contrast agent were inserted into holes bored through the phantom in the direction of varying glandularity. Various images of the phantom were acquired by altering the acquisition parameters (kV, mAs, and high bin fraction). A range of beam energies from 26 kV to 40 kV was tested in this study. Our results demonstrate that for a given contrast agent, the contrast-to-noise ratio (CNR) is linearly proportional to concentration, and its magnitude is dependent on the kV of the spectrum. At mammographic energies, the Ag2S-NP contrast increases with increasing kV and increasing solution concentration. Comparatively, the iodine signal becomes detectable only when the kV of the image is above iodine’s K-edge (33.2 keV). This indicates that the optimal energy for imaging iodine may exceed the clinical mammographic energy range. In summary, we have demonstrated the feasibility of using Ag2S-NP as a contrast agent for breast imaging. Preliminary results from spectral photon-counting mammography indicate that Ag2S-NP contrast has a significantly higher signal than iodine, especially when imaging at lower energies.

Lipoproteins are a set of natural nanoparticles whose main role is the transport of fats within the body. While much work has been done to develop synthetic nanocarriers to deliver drugs or contrast media, natural nanoparticles such as lipoproteins represent appealing alternatives. Lipoproteins are biocompatible, biodegradable, non-immunogenic and are naturally targeted to some disease sites. Lipoproteins can be modified to act as contrast agents in many ways, such as by insertion of gold cores to provide contrast for computed tomography. They can be loaded with drugs, nucleic acids, photosensitizers or boron to act as therapeutics. Attachment of ligands can re-route lipoproteins to new targets. These attributes render lipoproteins attractive and versatile delivery vehicles. In this review we will provide background on lipoproteins, then survey their roles as contrast agents, in drug and nucleic acid delivery, as well as in photodynamic therapy and boron neutron capture therapy.

Dental biofilms (known as plaque) are notoriously difficult to remove or treat because the bacteria can be enmeshed in a protective extracellular matrix. It can also create highly acidic microenvironments that cause acid-dissolution of enamel-apatite on teeth, leading to the onset of dental caries. Current antimicrobial agents are incapable of disrupting the matrix and thereby fail to efficiently kill the microbes within plaque-biofilms. Here, we report a novel strategy to control plaque-biofilms using catalytic nanoparticles (CAT-NP) with peroxidase-like activity that trigger extracellular matrix degradation and cause bacterial death within acidic niches of caries-causing biofilm. CAT-NP containing biocompatible Fe3O4 were developed to catalyze H2O2 to generate free-radicals in situ that simultaneously degrade the biofilm matrix and rapidly kill the embedded bacteria with exceptional efficacy (>5-log reduction of cell-viability). Moreover, it displays an additional property of reducing apatite demineralization in acidic conditions. Using 1-minute topical daily treatments akin to a clinical situation, we demonstrate that CAT-NP in combination with H2O2 effectively suppress the onset and severity of dental caries while sparing normal tissues in vivo. Our results reveal the potential to exploit nanocatalysts with enzyme-like activity as a potent alternative approach for treatment of a prevalent biofilm-associated oral disease.

Gold nanoparticles (AuNP) have been proposed for many applications in medicine. Although large AuNP (>5.5 nm) are desirable for their longer blood circulation and accumulation in diseased tissues, small AuNP (

Computed tomography (CT) is one of the most commonly used clinical imaging modalities. There have recently been many reports of novel contrast agents for CT imaging. In particular, the development of gold nanoparticles (AuNP) as CT contrast agents is a topic of intense interest. AuNP have favorable characteristics for this application such as high payloads of contrast generating material, strong X-ray attenuation, excellent biocompatibility, tailorable surface chemistry, and tunable sizes and shapes. However, there have been conflicting reports on the role of AuNP size on their contrast generation for CT. We therefore sought to extensively investigate the AuNP size-CT contrast relationship. In order to do this, we synthesized AuNP with sizes ranging from 4 to 152 nm and capped them with 5 kDa m-PEG. The contrast generation of AuNP of different sizes was investigated with three clinical CT, a spectral photon counting CT (SPCCT) and two micro CT systems. X-ray attenuation was quantified as attenuation rate in Hounsfield units per unit concentration (HU/mM). No statistically significant difference in CT contrast generation was found among different AuNP sizes via phantom imaging with any of the systems tested. Furthermore, in vivo imaging was performed in mice to provide insight into the effect of AuNP size on animal biodistribution at CT dose levels, which has not previously been explored. Both in vivo imaging and ex vivo analysis with inductively coupled plasma optical emission spectroscopy (ICP-OES) indicated that AuNP that are 15 nm or smaller have long blood circulation times, while larger AuNP accumulated in the liver and spleen more rapidly. Therefore, while we observed no AuNP size effect on CT contrast generation, there is a significant effect of size on AuNP diagnostic utility.

Nanostructures have potential for use in biomedical applications such as sensing, imaging, therapeutics, and drug delivery. Among nanomaterials, gold nanostructures are of considerable interest for biomedical research, owing to their bio-inertness, controllable surface chemistry, X-ray opacity, and optical properties. Gold nanocages are particularly attractive for imaging and therapeutic applications, because they strongly absorb light in the near infra-red region which has high light transmission in tissue. However, the X-ray attenuation of nanocages is relatively low due to their hollow structure. In this study, for the first time, we sought to combine the attractive optical properties of nanoshells with the high payloads of solid nanoparticles and investigated their biomedical applications. Here, we report the engineering of Wulff in a cage nanoparticles via converting gold Wulff-shaped seeds into gold-silver core-shell structures and then performing a galvanic replacement reaction. The structure of these nanoparticles was determined using transition electron microscopy. This morphological transformation of gold nanoparticles shaped as truncated octahedrons into a complex Wulff in a cage nanoparticles during the reaction resulted in extensive changes in their optical properties that made these unique structures a potential contrast agent for photoacoustic imaging. We found that the Wulff in a cage nanoparticles had no adverse effects on the viabilities of J774A.1, Renca, and HepG2 cells at any of the concentrations tested. In vitro and in vivo experiments showed robust signals in both photoacoustic imaging and computed tomography. To the best of our knowledge, this is the first report of Wulff in a cage nanoparticles serving as a platform for multiple imaging modalities. This unique multifunctional nanostructure, which integrates the competencies of both core and shell structures, allows their use as contrast agents for photoacoustic imaging, computed tomography and as a potential agent for photothermal therapy.

Supplemental digital content is available in the text., Objectives To validate in vitro the capability of a high-spatial-resolution prototype spectral photon-counting computed tomography (SPCCT) scanner to differentiate between 2 contrast agents and to assess in vivo the image quality and the feasibility to image the peritoneal cavity in rats using the 2 contrast agents simultaneously within the vascular and peritoneal compartments. Materials and Methods The authors performed SPCCT imaging (100 mAs, 120 kVp) with energy bin thresholds set to 30, 51, 64, 72, and 85 keV in vitro on a custom-made polyoxymethylene cylindrical phantom consisting of tubes with dilutions of both contrast agents and in vivo on 2 groups of adult rats using 2 injection protocols. Approval from the institutional animal ethics committee was obtained. One group received macrocylic gadolinium chelate intraperitoneal (IP) and iodine intravenous (IV) injections (protocol A, n = 3), whereas the second group received iodine IP and gadolinium IV (protocol B, n = 3). Helical scans were performed 35 minutes after IP injection and 20 seconds after IV injection. The SPCCT and contrast material images, that is, iodine and gadolinium maps, were reconstructed with a field of view of 160 mm, an isotropic voxel size of 250 μm, and a matrix size of 640 × 640 pixels using a soft reconstruction kernel. The SPCCT images were reconstructed with 2 different spatial resolutions to compare the image quality (sharpness, diagnostic quality, and organ visualization) of SPCCT (250 μm) with single-energy computed tomography (CT) (600 μm). Two radiologists evaluated the peritoneal opacification index in 13 regions (score = 0–3 per region) on each type of image. Concentrations of contrast agents were measured in the organs of interest. Results In vitro, the concentration measurements correlated well with the expected concentrations. The linear regressions both had R2 values of 0.99, slopes of 0.84 and 0.87, and offsets at −0.52 and −0.38 mg/mL for iodine and gadolinium, respectively. In vivo, the SPCCT images were of better diagnostic quality, with increased sharpness compared with the CT-like images (P < 0.0001). Intraperitoneal diffusion was excellent, with similar peritoneal opacification index on SPCCT images and overlay of contrast material maps (P = 1) without a significant difference between protocol A (37.0 ± 1.7) and protocol B (35.3 ± 1.5) (P = 0.34). Only the contrast material maps demonstrated clear visual separation of the contrast agents, allowing specific quantification of the physiological enhancement in the liver, spleen, and kidney and the urinary clearance in the renal pelvis and bladder. Renal excretion of the contrast agents injected IP was observed and was consistent with blood diffusion. Conclusions Spectral photon-counting CT can be used to perform a complete peritoneal dual-contrast protocol, enabling a good assessment of the peritoneal cavity and abdominal organs in rats.