Ceria-Based Therapeutic Antioxidants for Biomedical Applications.

The growing interest in nanomedicine over the last 20 years has carved out a research field called "nanocatalytic therapy," where catalytic reactions mediated by nanomaterials are employed to intervene in disease-critical biomolecular processes. Among many kinds of catalytic/enzyme-mimetic nanomaterials investigated thus far, ceria nanoparticles stand out from others owing to their unique scavenging properties against biologically noxious free radicals, including reactive oxygen species (ROS) and reactive nitrogen species (RNS), by exerting enzyme mimicry and nonenzymatic activities. Much effort has been made to utilize ceria nanoparticles as self-regenerating antioxidative and anti-inflammatory agents for various kinds of diseases, given the detrimental effects of ROS and RNS therein that need alleviation. In this context, this review is intended to provide an overview as to what makes ceria nanoparticles merit attention in disease therapy. The introductory part describes the characteristics of ceria nanoparticles as an oxygen-deficient metal oxide. The pathophysiological roles of ROS and RNS are then presented, as well as their scavenging mechanisms by ceria nanoparticles. Representative examples of recent ceria-nanoparticle-based therapeutics are summarized by categorization into organ and disease types, followed by the discussion on the remaining challenges and future research directions.

Inorganic nanoparticle agents for enhanced chemodynamic therapy of tumours.

With the recent interest in the role of oxidative species/radicals in diseases, inorganic nanomaterials with redox activities have been extensively investigated for their potential use in nanomedicine. While many studies focusing on relieving oxidative stress to prevent pathogenesis and to suppress the progression of diseases have shown considerable success, another approach for increasing oxidative stress using nanomaterials to kill malignant cells has suffered from low efficiency despite its wide applicability to various targets. Chemodynamic therapy (CDT) is an emerging technique that can resolve such a problem by exploiting the characteristic tumour microenvironment to achieve high selectivity. In this review, we summarize the recent strategies and underlying mechanisms that have been used to improve the CDT performance using inorganic nanoparticles. In addition to the design of CDT agents, the effects of contributing factors, such as the acidity and the levels of hydrogen peroxide and antioxidants in the tumour microenvironment, together with their modulation and application in combination therapy, are presented. The challenges lying ahead of future clinical translation of this rapidly advancing technology are also discussed.

Structural Color Mixing in Microcapsules through Exclusive Crystallization of Binary and Ternary Colloids.

Colloidal crystals are designed as photonic microparticles for various applications. However, conventional microparticles generally have only one stopband from a single lattice constant, which restricts the range of colors and optical codes available. Here, photonic microcapsules are created that contain two or three distinct crystalline grains, resulting in dual or triple stopbands that offer a wider range of colors through structural color mixing. To produce distinct colloidal crystallites from binary or ternary colloidal mixtures, the interparticle interaction is manipulated using depletion forces in double-emulsion droplets. Aqueous dispersions of binary or ternary colloidal mixtures in the innermost droplet are gently concentrated in the presence of a depletant and salt by imposing hypertonic conditions. Different-sized particles crystallize into their own crystals rather than forming random glassy alloys to minimize free energy. The average size of the crystalline grains can be adjusted with osmotic pressure, and the relative ratio of distinct grains can be controlled with the mixing ratio of particles. The resulting microcapsules with small grains and high surface coverage are almost optically isotropic and exhibit highly-saturated mixed structural colors and multiple reflectance peaks. The mixed color and reflectance spectrum are controllable with the selection of particle sizes and mixing ratios.

Centrifugation-Assisted Growth of Single-Crystalline Grains in Microcapsules.

Colloidal crystals have been tailored in a format of microspheres to use them as a building block to construct macroscopic photonic surfaces. However, the polycrystalline grains grown from the spherical surface usually exhibit low reflectivity. Although single-crystalline microspheres have been produced, it is difficult to control the crystal orientation. Here, we design spherical microcapsules with density anisotropy that contain single-crystalline grains along the heavy side. The microcapsules spontaneously align to have a heavy side down under the action of gravity and display a bright and uniform reflection color from the entire surface of the grains. Key to the success is the use of gentle centrifugal force to initiate nucleation and grow single-crystalline grains from the heavy side through depletion attraction. The microcapsules have density anisotropy due to the heterogeneity of the shell thickness, which causes them to self-align under centrifugation. At the same time, particles are accumulated on the heavy side, which produces many tiny grains on the heavy side immediately after the centrifugation. With controlled depletion attraction among particles, only a few grains survive during postincubation through Ostwald ripening, and one or a few giant single-crystalline grains are finally produced along the heavy side of each microcapsule.

Ceria Nanoparticles as Copper Chaperones that Activate SOD1 for Synergistic Antioxidant Therapy to Treat Ischemic Vascular Diseases.

All exogenous nanomaterials undergo rapid biotransformation once injected into the body and fall short of executing the intended purpose. Here, it is reported that copper-deposited ceria nanoparticles (CuCe NPs) exhibit enhanced antioxidant effects over pristine ceria nanoparticles, as the released copper buffers the depletion of glutathione while providing the bioavailable copper as a cofactor for the antioxidant enzyme, superoxide dismutase 1. The upregulated intracellular antioxidants along with the ceria nanoparticles synergistically scavenge reactive oxygen species and promote anti-inflammation and M2 polarization of macrophages by modulating signal transducer and activator of transcription 1 and 6 (STAT1 and STAT6). The therapeutic effect of CuCe NPs is demonstrated in ischemic vascular diseases (i.e., murine models of hindlimb ischemia and myocardial infarction) in which the copper-deposition affords increased perfusion and alleviation in tissue damage. The results provide rationale that metal oxide nanomaterials can be designed in a way to induce the upregulation of specific biological factors for optimal therapeutic performance.

Designing photonic microparticles with droplet microfluidics.

Photonic materials with a periodic change of refractive index show unique optical properties through wavelength-selective diffraction and modulation of the optical density of state, which is promising for various optical applications. In particular, photonic structures have been produced in the format of microparticles using emulsion templates to achieve advanced properties and applications beyond those of a conventional film format. Photonic microparticles can be used as a building block to construct macroscopic photonic materials, and the individual microparticles can serve as miniaturized photonic devices. Droplet microfluidics enables the production of emulsion drops with a controlled size, composition, and configuration that serve as the optimal confining geometry for designing photonic microparticles. This feature article reviews the recent progress and current state of the art in the field of photonic microparticles, covering all aspects of microfluidic production methods, microparticle geometries, optical properties, and applications. Two distinct bottom-up approaches based on colloidal assembly and liquid crystals are, respectively, discussed and compared.

Facile and Scalable Synthesis of Whiskered Gold Nanosheets for Stretchable, Conductive, and Biocompatible Nanocomposites.

Noble metal nanomaterials have been studied as conductive fillers for stretchable, conductive, and biocompatible nanocomposites. However, their performance as conductive filler materials is far from ideal because of their high percolation threshold and low intrinsic conductivity. Moreover, the difficulty in large-scale production is another critical hurdle in their practical applications. Here we report a method for the facile and scalable synthesis of whiskered gold nanosheets (W-AuNSs) for stretchable, conductive, and biocompatible nanocomposites and their application to stretchable bioelectrodes. W-AuNSs show a lower percolation threshold (1.56 vol %) than those of gold nanoparticles (5.02 vol %) and gold nanosheets (2.74 vol %), which enables the fabrication of W-AuNS-based stretchable nanocomposites with superior conductivity and high stretchability. Addition of platinum-coated W-AuNSs (W-AuNSs@Pt) to the prepared nanocomposite significantly reduces the impedance and improved charge storage capacity. Such enhanced performance of the stretchable nanocomposite enables us to fabricate stretchable bioelectrodes whose performance is demonstrated through animal experiments including electrophysiological recording and electrical stimulation in vivo.

Effect of polystyrene nanoplastics and their degraded forms on stem cell fate.

Several studies have examined the effects of micro- and nanoplastics on microbes, cells, and the environment. However, only a few studies have examined their effects-especially, those of their reduced cohesiveness-on cell viability and physiology. We synthesized surfactant-free amine-functionalized polystyrene (PS) nanoparticles (NPs) and PS-NPs with decreased crosslinking density (DPS-NPs) without changing other factors, such as size, shape, and zeta potential and examined their effects on cell viability and physiology. PS- and DPS-NPs exhibited reactive oxygen species (ROS) scavenging activity by upregulating GPX3 expression and downregulating HSP70 (ROS-related gene) and XBP1 (endoplasmic reticulum stress-related gene) expression in human bone marrow-derived mesenchymal stem cells (hBM-MSCs). Additionally, they led to upregulation of MFN2 (mitochondrial fusion related gene) expression and downregulation of FIS1 (mitochondrial fission related gene) expression, indicating enhanced mitochondrial fusion in hBM-MSCs. Cell-cycle analysis revealed that PS- and DPS-NPs increased the proportion of cells in the S phase, indicating that they promoted cell proliferation and, specifically, the adipogenic differentiation of hBM-MSCs. However, the cytotoxicity of DPS-NPs against hBM-MSCs was higher than that of PS-NPs after long-term treatment under adipogenic conditions.

Enhanced Chemodynamic Therapy by Cu-Fe Peroxide Nanoparticles: Tumor Microenvironment-Mediated Synergistic Fenton Reaction.

An urgent need in chemodynamic therapy (CDT) is to achieve high Fenton catalytic efficiency at small doses of CDT agents. However, simple general promotion of the Fenton reaction increases the risk of damaging normal cells along with the cancer cells. Therefore, a tailored strategy to selectively enhance the Fenton reactivity in tumors, for example, by taking advantage of the characteristics of the tumor microenvironment (TME), is in high demand. Herein, a heterogeneous CDT system based on copper-iron peroxide nanoparticles (CFp NPs) is designed for TME-mediated synergistic therapy. CFp NPs degrade under the mildly acidic conditions of TME, self-supply H2O2, and the released Cu and Fe ions, with their larger portions at lower oxidation states, cooperatively facilitate hydroxyl radical production through a highly efficient catalytic loop to achieve an excellent tumor therapeutic efficacy. This is distinct from previous heterogeneous CDT systems in that the synergism is closely coupled with the Cu+-assisted conversion of Fe3+ to Fe2+ rather than their independent actions. As a result, almost complete ablation of tumors at a minimal treatment dose is demonstrated without the aid of any other therapeutic modality. Furthermore, CFp NPs generate O2 during the catalysis and exhibit a TME-responsive T1 magnetic resonance imaging contrast enhancement, which are useful for alleviating hypoxia and in vivo monitoring of tumors, respectively.

In Vivo Sol-Gel Reaction of Tantalum Alkoxide for Endovascular Embolization.

Liquid embolic agents are considered the most promising for various embolization procedures because they enable deep penetration. For realizing effective procedures, the delivery of liquid embolic agents should be guided under X-ray imaging systems and the solidification time should be optimized for the specific indication. The biocompatibility of embolic agents is also crucial because they remain in the vessel after embolization. In this study, new biocompatible embolic agents based on tantalum ethoxide is synthesized. Tantalum alkoxide liquid embolics (TALE) possess the radiopacity for fluoroscopy and can control the penetration depth by modifying the sol-gel kinetics. Furthermore, TALE can serve as drug carriers for synergistic treatment. Using these excellent characteristics, it is demonstrated that TALE agents can be used in various situations including the transarterial chemoembolization of hepatocellular carcinoma and embolotherapy of massive bleeding from the femoral artery.

Elastic Photonic Microcapsules Containing Colloidal Crystallites as Building Blocks for Macroscopic Photonic Surfaces.

Colloidal crystals develop structural colors through wavelength-selective diffraction. Recently, a granular format of colloidal crystals has emerged as building blocks to construct macroscopic photonic surfaces or architectures with high reconfigurability through the secondary assembly. Here, we design elastic photonic microcapsules containing colloidal crystallites along the inner wall as a building block. Water-in-oil-in-water double-emulsion templates are microfluidically prepared to have an aqueous dispersion of polystyrene particles in the inner droplet and polydimethylsiloxane prepolymers in the shell. Colloidal particles are enriched in the presence of depletant and salt by osmotic compression, with the crystallization at the inner interface by depletion attraction. The number of nucleation sites depends on the rate of the enrichment, which enables control over the size and surface coverage of the crystallites with osmotic conditions. The enrichment is ceased by transferring the droplets into an isotonic solution, and the oil shell is cured to form an elastic membrane. As the elastic microcapsules have a large void in the core, they are deformable without structural damage in the crystallites. Therefore, the microcapsules can be closely packed to form macroscopic surfaces while achieving a high quality of structural colors with a collection of crystallites aligned along the flattened membrane.

Ceria Nanoparticle Systems for Selective Scavenging of Mitochondrial, Intracellular, and Extracellular Reactive Oxygen Species in Parkinson's Disease.

Oxidative stress induced by reactive oxygen species (ROS) is one of the critical factors that involves in the pathogenesis and progression of many diseases. However, lack of proper techniques to scavenge ROS depending on their cellular localization limits a thorough understanding of the pathological effects of ROS. Here, we demonstrate the selective scavenging of mitochondrial, intracellular, and extracellular ROS using three different types of ceria nanoparticles (NPs), and its application to treat Parkinson's disease (PD). Our data show that scavenging intracellular or mitochondrial ROS inhibits the microglial activation and lipid peroxidation, while protecting the tyrosine hydroxylase (TH) in the striata of PD model mice. These results indicate the essential roles of intracellular and mitochondrial ROS in the progression of PD. We anticipate that our ceria NP systems will serve as a useful tool for elucidating the functions of various ROS in diseases.

Association between blood glucose level derived using the oral glucose tolerance test and glycated hemoglobin level.

BACKGROUND/AIMS: Glycated hemoglobin (HbA1c) is widely used as a marker of glycemic control. Translation of the HbA1c level to an average blood glucose level is useful because the latter figure is easily understood by patients. We studied the association between blood glucose levels revealed by the oral glucose tolerance test (OGTT) and HbA1c levels in a Korean population. METHODS: A total of 1,000 subjects aged 30 to 64 years from the Cardiovascular and Metabolic Diseases Etiology Research Center cohort were included. Fasting glucose levels, post-load glucose levels at 30, 60, and 120 minutes into the OGTT, and HbA1c levels were measured. RESULTS: Linear regression of HbA1c with mean blood glucose levels derived using the OGTT revealed a significant correlation between these measures (predicted mean glucose [mg/dL] = 49.4 × HbA1c [%] - 149.6; R (2) = 0.54, p < 0.001). Our linear regression equation was quite different from that of the Alc-Derived Average Glucose (ADAG) study and Diabetes Control and Complications Trial (DCCT) cohort. CONCLUSIONS: Discrepancies between our results and those of the ADAG study and DCCT cohort may be attributable to differences in the test methods used and the extent of insulin secretion. More studies are needed to evaluate the association between HbA1c and self monitoring blood glucose levels.