Ultrasmall polymer-coated cerium oxide nanoparticles as a traumatic brain injury therapy.

No medication has been approved for secondary injuries after traumatic brain injury (TBI). While free radicals are considered a major mediator of secondary injury, conventional antioxidants only have modest clinical efficacy. Here, we synthesized CX201 consisting of core cerium oxide nanoparticles coated with 6-aminocaproic acid and polyvinylpyrrolidone in aqueous phase. CX201 with 3.49 ± 1.11 nm of core and 6.49 ± 0.56 nm of hydrodynamic diameter showed multi-enzymatic antioxidant function. Owing to its excellent physiological stability and cell viability, CX201 had a neuroprotective effect in vitro. In a TBI animal model, an investigator-blinded randomized experiment showed a single intravenously injected CX201 significantly improved functional recovery compared to the control. CX201 reduced lipid peroxidation and inflammatory cell recruitment at the damaged brain. These suggest ultrasmall CX201 can efficiently reduce secondary brain injuries after TBI. Given the absence of current therapies, CX201 may be proposed as a novel therapeutic strategy for TBI.

Alternative Activation of Macrophages through Interleukin-13-Loaded Extra-Large-Pore Mesoporous Silica Nanoparticles Suppresses Experimental Autoimmune Encephalomyelitis.

Multiple sclerosis (MS) treatment via cytokine-mediated immunomodulation has been hampered by the difficulty with which cytokines can be stably and noninvasively delivered to the central nervous system. Here, we show that interleukin (IL)-13 packaged in extra-large-pore mesoporous silica nanoparticles (XL-MSNs) is protected from degradation and directs the alternative activation of macrophages both in vitro and in vivo. Furthermore, the noninvasive intranasal delivery of IL-13-loaded XL-MSNs ameliorated the symptoms of experimental autoimmune encephalomyelitis, a murine model of MS, accompanied by the induction of chemokines orchestrating immune cell infiltration. These results demonstrate the therapeutic potential of IL-13-loaded XL-MSNs for MS patients.

Injectable dual-scale mesoporous silica cancer vaccine enabling efficient delivery of antigen/adjuvant-loaded nanoparticles to dendritic cells recruited in local macroporous scaffold.

Despite the potential of nanoparticle-based vaccines, their therapeutic efficacy for cancer immunotherapy is limited. To elicit robust antigen-specific adaptive immune responses, antigen-loaded nanoparticles are employed for transport into host dendritic cells (DCs); however, only a minority of the nanoparticles can be engulfed by host DCs. Herein, an injectable dual-scale mesoporous silica vaccine consisting of mesoporous silica microrods (MSRs) coupled with mesoporous silica nanoparticles (MSNs) is introduced. The MSRs form a three-dimensional macroporous scaffold after injection, and the subsequent release of DC-recruiting chemokine loaded in the mesopores of MSRs leads to the recruitment of numerous DCs into the scaffold. Subsequently, MSNs co-loaded with an antigen and Toll-like receptor 9 agonist, which exist in interparticle space of the MSR scaffold, are internalized by the recruited DCs, leading to the generation of antigen-presenting activated DCs. Strikingly, the MSR-MSN dual-scale vaccine generates a significantly larger number of antigen-specific T cells and inhibits melanoma growth to a greater extent compared with a single MSR or MSN vaccine. Moreover, the dual-scale vaccine is synergized with an immune checkpoint inhibitor to inhibit tumor growth in tumor-bearing mice. The findings suggest that the MSR is a novel platform for delivering nanoparticle vaccines for the enhancement of cancer immunotherapy.

Therapeutic Contact Lens for Scavenging Excessive Reactive Oxygen Species on the Ocular Surface.

Excessive reactive oxygen species (ROS) play a significant role in the pathogenesis of many eye diseases. Controlling oxidative stress by reducing the amount of ROS is a potential therapeutic strategy for the prevention and treatment of eye diseases, particularly ocular surface diseases. Ceria nanoparticles (CeNPs) have been investigated owing to their efficient ROS-scavenging properties. To overcome the disadvantages of eyedrop administration due to rapid elimination on the surface of the eye and to retain the intrinsic properties of contact lenses, we developed an ROS-scavenging water-soluble CeNP-embedded contact lens (CeNP-CL) for the prevention of ocular surface diseases. The intrinsic ROS-scavenging property of the CeNPs, which mimicked the activities of superoxide dismutase and catalase, was incorporated into polyhydroxyethyl methacrylate-based contact lenses. The CeNP-CL exhibited high transparency and physical properties comparable to those of a commercial contact lens, along with excellent extracellular ROS-scavenging properties. The viabilities of human conjunctival epithelial cells and human meibomian gland epithelial cells were significantly enhanced in the presence of CeNP-CLs, even in media with high H2O2 contents (100 and 500 µM). Additionally, the wearing of CeNP-CLs on the eyes had a protective effect in a mouse model when 3% H2O2 eyedrops were administered. These results indicate the salvaging effect of the CeNP-CL in a high-ROS environment on the ocular surface, which may be helpful for the treatment of ocular surface diseases.

Ceria Nanoparticles Fabricated with 6-Aminohexanoic Acid that Overcome Systemic Inflammatory Response Syndrome.

Systemic inflammatory response syndrome (SIRS) is self-destructive and uncontrollable inflammatory response of the whole body triggered by infection, trauma, or a variety of severe injuries. Although reactive oxygen species play a pivotal role in the development of SIRS, the trials with conventional antioxidants have failed to improve patient outcome. Ceria nanoparticles (CeNPs) have potent, autocatalytic reactive oxygen species scavenging activities, which may have sufficient therapeutic effects for SIRS. Herein, 3 nm CeNPs are fabricated totally in aqueous phase by using 6-aminohexanoic acid (6-AHA) and their Ce3+ to Ce4+ ratio is increased to enhance antioxidative properties. The obtained 6-AHA-CeNPs demonstrate strong antioxidative and anti-inflammatory effects in various biofluids and inflammatory cells. In SIRS animal models, 6-AHA-CeNPs are demonstrated to reduce multiple organ injuries and inflammation. Moreover, 6-AHA-CeNPs decrease mortality and improve clinical scores of SIRS models. These findings suggest that 6-AHA-CeNPs have potential as a therapeutic nanomedicine for SIRS.

Mesoporous Silica Nanoparticles Doped with Gold Nanoparticles for Combined Cancer Immunotherapy and Photothermal Therapy.

Cancer immunotherapy is a treatment that utilizes the host immune system to fight against cancer. Inducing a cancer antigen-specific adaptive immune response is key in cancer immunotherapy. Although diverse immune cells including dendritic cells (DCs) and T cells infiltrate a tumor, the activation of such immune cells is inhibited, owing to an immunosuppressive tumor microenvironment. In this study, we propose mesoporous silica nanoparticles (XL-MSNs) decorated with gold nanoparticles (Au@XL-MSNs) for the delivery of a high amount of CpG-ODNs to the tumor site to activate DCs infiltrated within the tumor for the induction of an antigen-specific adaptive immune response. During an in vitro test, CpG-ODNs delivered using Au@XL-MSNs were shown to be more effectively internalized by bone-marrow-derived dendritic cells (BMDCs), resulting in an enhanced expression of costimulatory molecules and an increased secretion of pro-inflammatory cytokines compared to soluble CpG-ODNs. Furthermore, an in vivo test demonstrated a more significant tumor growth inhibition and an enhanced survival rate result from the intratumoral injection of Au@XL-MSN-CpG compared to that treated using soluble CpG-ODNs. Furthermore, through the induction of a photothermal effect based on the assembled AuNPs on XL-MSNs, an enhancement of the cancer immunotherapy was achieved by generating a cancer antigen at the tumor site, which can be processed by tumor-infiltrated DCs. These findings suggest that our approach can be applied as a synergistic platform for efficient cancer immunotherapy, enabling a delivery of immunostimulating signals as well as in situ antigen generation through a photothermal effect.

Functional mesoporous silica nanoparticles for bio-imaging applications.

Biomedical investigations using mesoporous silica nanoparticles (MSNs) have received significant attention because of their unique properties including controllable mesoporous structure, high specific surface area, large pore volume, and tunable particle size. These unique features make MSNs suitable for simultaneous diagnosis and therapy with unique advantages to encapsulate and load a variety of therapeutic agents, deliver these agents to the desired location, and release the drugs in a controlled manner. Among various clinical areas, nanomaterials-based bio-imaging techniques have advanced rapidly with the development of diverse functional nanoparticles. Due to the unique features of MSNs, an imaging agent supported by MSNs can be a promising system for developing targeted bio-imaging contrast agents with high structural stability and enhanced functionality that enable imaging of various modalities. Here, we review the recent achievements on the development of functional MSNs for bio-imaging applications, including optical imaging, magnetic resonance imaging (MRI), positron emission tomography (PET), computed tomography (CT), ultrasound imaging, and multimodal imaging for early diagnosis. With further improvement in noninvasive bio-imaging techniques, the MSN-supported imaging agent systems are expected to contribute to clinical applications in the future. This article is categorized under: Diagnostic Tools > In vivo Nanodiagnostics and Imaging Nanotechnology Approaches to Biology > Nanoscale Systems in Biology.

Ceria Nanoparticles Synthesized With Aminocaproic Acid for the Treatment of Subarachnoid Hemorrhage.

Background and Purpose- Despite early aneurysm repair and aggressive management for complications, subarachnoid hemorrhage (SAH) results in at least 25% mortality rate and 50% persistent neurological deficit. We investigated whether ceria nanoparticles which have potent antioxidative activities can protect against subarachnoid hemorrhage via attenuating fatal brain injuries. Methods- Uniform, 3 nm, water-dispersed ceria nanoparticles were prepared from short sol-gel reaction of cerium (III) ions with aminocaproic acid in aqueous phase. SAH was induced by endovascular perforation of middle cerebral artery of rats. A single dose of ceria nanoparticles (0.5 mg Ce/kg) or saline control was randomly administered intravenously at an hour post-SAH. Neuronal death, macrophage infiltration, SAH grade, and brain edema were evaluated at 72 hours. Mortality and neurological function were assessed for 14 days. Results- The obtained ceria nanoparticles with high Ce3+ to Ce4+ ratio demonstrated potent antioxidative, cytoprotective, and anti-inflammatory activities in vitro. In rodent SAH models, the severity of hemorrhage was comparable between the ceria nanoparticles- and saline-treated groups. However, ceria nanoparticles significantly reduced neuronal death, macrophage infiltration, and brain edema after SAH. Ceria nanoparticles successfully improved survival rates (88.2% in the ceria nanoparticles group versus 21.1% in the control group; P<0.001) and neurological outcomes (modified Garcia score: 12.1±0.5 in the ceria nanoparticles group versus 4.4±0.5 in the control group; P<0.001) of the animals with SAH. Conclusions- Ceria nanoparticles, totally synthesized in aqueous phase using aminocaproic acid, demonstrated promising results against SAH via potent antioxidative, neuroprotective and anti-inflammatory activities. Given the obvious limitations of current therapies for SAH, ceria nanoparticles can be a potential therapeutic agent which might result in a paradigm shift in SAH treatment.

Extra-Large Pore Mesoporous Silica Nanoparticles Enabling Co-Delivery of High Amounts of Protein Antigen and Toll-like Receptor 9 Agonist for Enhanced Cancer Vaccine Efficacy.

Cancer vaccine aims to invoke antitumor adaptive immune responses to detect and eliminate tumors. However, the current dendritic cells (DCs)-based cancer vaccines have several limitations that are mostly derived from the ex vivo culture of patient DCs. To circumvent the limitations, direct activation and maturation of host DCs using antigen-carrying materials, without the need for isolation of DCs from patients, are required. In this study, we demonstrate the synthesis of extra-large pore mesoporous silica nanoparticles (XL-MSNs) and their use as a prophylactic cancer vaccine through the delivery of cancer antigen and danger signal to host DCs in the draining lymph nodes. Extra-large pores of approximately 25 nm and additional surface modification of XL-MSNs resulted in significantly higher loading of antigen protein and toll-like receptor 9 (TLR9) agonist compared with conventional small-pore MSNs. In vitro study showed the enhanced activation and antigen presentation of DCs and increased secretion of proinflammatory cytokines. In vivo study demonstrated efficient targeting of XL-MSNs co-delivering antigen and TLR9 agonist to draining lymph nodes, induction of antigen-specific cytotoxic T lymphocytes (CTLs), and suppression of tumor growth after vaccination. Furthermore, significant prevention of tumor growth after tumor rechallenge of the vaccinated tumor-free mice resulted, which was supported by a high level of memory T cells. These findings suggest that mesoporous silica nanoparticles with extra-large pores can be used as an attractive platform for cancer vaccines.

Injectable Macroporous Ferrogel Microbeads with a High Structural Stability for Magnetically Actuated Drug Delivery.

Macroporous hydrogels are an attractive material platform that can provide shortened interfacial diffusion pathways and high biomacromolecule loading. Recently, macroporous ferrogels have shown high potential for use in the on-demand delivery of bioactive molecules, resulting from their reversible and large volumetric deformation upon magnetic stimulation. However, these macroporous ferrogels require surgical placement in the body due to their large size; an injectable form of macroporous ferrogels has not yet been reported. In this study, injectable macroporous ferrogel microbeads loaded with iron oxide nanoparticles have been prepared on the basis of alginate microbeads for on-demand drug release. A simple solvent exchange and subsequent covalent cross-linking of the alginate chains in hydrogel microbeads induced a high polymer density on the hydrogel network and led to enhanced mechanical properties even after the generation of macropores in the microbeads. The macroporous ferrogel microbeads exhibited good mechanical stability and were stable during needle injection. The increased loading of large biomolecules due to the macroporosity of the microbeads and their large reversible volumetric deformation response to the external magnetic field enabled their potential for use in the on-demand delivery of drugs of assorted sizes by magnetic actuation. As a result of their structural stability, injectable size, and ability for on-demand drug delivery, ferrogel microbeads have promising potential for application in many biomedical fields.

Extra-Large Pore Mesoporous Silica Nanoparticles for Directing in Vivo M2 Macrophage Polarization by Delivering IL-4.

Over the past decade, mesoporous silica nanoparticles (MSNs) smaller than 200 nm with a high colloidal stability have been extensively studied for systemic drug delivery. Although small molecule delivery via MSNs has been successful, the encapsulation of large therapeutic biomolecules, such as proteins or DNA, is limited due to small pore size of the conventional MSNs obtained by soft-templating. Here, we report the synthesis of mesoporous silica nanoparticles with extra-large pores (XL-MSNs) and their application to in vivo cytokine delivery for macrophage polarization. Uniform, size-controllable XL-MSNs with 30 nm extra-large pores were synthesized using organic additives and inorganic seed nanoparticles. XL-MSNs showed significantly higher loadings for the model proteins with different molecular weights compared to conventional small pore MSNs. XL-MSNs were used to deliver IL-4, which is an M2-polarizing cytokine and very quickly degraded in vivo, to macrophages and polarize them to anti-inflammatory M2 macrophages in vivo. XL-MSNs induced a low level of reactive oxygen species (ROS) production and no pro-inflammatory cytokines in bone marrow-derived macrophages (BMDMs) and in mice injected intravenously with XL-MSNs. We found that the injected XL-MSNs were targeted to phagocytic myeloid cells, such as neutrophils, monocytes, macrophages, and dendritic cells. Finally, we demonstrated that the injection of IL-4-loaded XL-MSNs successfully triggered M2 macrophage polarization in vivo, suggesting the clinical potential of XL-MSNs for modulating immune systems via targeted delivery of various cytokines.

Self-Position of Au NPs in Perovskite Solar Cells: Optical and Electrical Contribution.

Metallic nanoparticles (NPs) exhibit a localized surface plasmon resonance (LSPR) and act as scattering centers and subwavelength antennas, so metallic NPs can be incorporated into perovskite solar cells (PSCs) to effectively improve the light absorption of light harvesting devices. Here, we have embedded Au nanoparticles (NPs) into the hole transport layer (HTL) of the PSCs to investigate the photovoltaic effect of the PSCs with Au NPs. Interestingly, it was found that Au NPs dispersed spiro-OMeTAD HTL solution could naturally end up located near the perovskite layer as the result of the spin-coating step. Solar cell performance observations indicate that the LSPR and electrical effects of Au NPs enhance the photovoltaic response of PSCs, in spite of a slight decrease in the open-circuit voltage (VOC), by causing an incredible improvement in the photocurrent density as a dominant factor.

Tongue Growth during Prenatal Development in Korean Fetuses and Embryos.

BACKGROUND: Prenatal tongue development may affect oral-craniofacial structures, but this muscular organ has rarely been investigated. METHODS: In order to document the physiology of prenatal tongue growth, we histologically examined the facial and cranial base structures of 56 embryos and 106 fetuses. RESULTS: In Streeter's stages 13-14 (fertilization age [FA], 28 to 32 days), the tongue protruded into the stomodeal cavity from the retrohyoid space to the cartilaginous mesenchyme of the primitive cranial base, and in Streeter's stage 15 (FA, 33 to 36 days), the tongue rapidly swelled and compressed the cranial base to initiate spheno-occipital synchondrosis and continued to swell laterally to occupy most of the stomodeal cavity in Streeter's stage 16-17 (FA, 37 to 43 days). In Streeter's stage 18-20 (FA, 44 to 51 days), the tongue was vertically positioned and filled the posterior nasopharyngeal space. As the growth of the mandible and maxilla advanced, the tongue was pulled down and protruded anteriorly to form the linguomandibular complex. Angulation between the anterior cranial base (ACB) and the posterior cranial base (PCB) was formed by the emerging tongue at FA 4 weeks and became constant at approximately 124°-126° from FA 6 weeks until birth, which was consistent with angulations measured on adult cephalograms. CONCLUSIONS: The early clockwise growth of the ACB to the maxillary plane became harmonious with the counter-clockwise growth of the PCB to the tongue axis during the early prenatal period. These observations suggest that human embryonic tongue growth affects ACB and PCB angulation, stimulates maxillary growth, and induces mandibular movement to achieve the essential functions of oral and maxillofacial structures.

Tailoring dispersion and aggregation of Au nanoparticles in the BHJ layer of polymer solar cells: plasmon effects versus electrical effects.

Plasmonic effects that arise from embedding metallic nanoparticles (NPs) in polymer solar cells (PSCs) have been extensively studied. Many researchers have utilized metallic NPs in PSCs by either incorporating them into the PSC interlayers (e.g., the hole extraction and electron extraction layers) or blending them into the bulk heterojunction (BHJ) active layer. In such studies, the dispersity of the metallic NPs in each layer may vary due to both the different nature of the ligands and the amount of ligands on the metallic NPs. This in turn can produce different PSC performance parameters. Here, we systematically control the amount of attached organic ligands on Au NPs to control their dispersion behavior in the BHJ active layer of PSCs. By controlling the number of capping organic ligands on the Au NPs, the dispersity of the NPs in the BHJ layer is also controlled and the positive effects (particularly the plasmonic and electrical effects) of the Au NPs in the PSCs are investigated. From the obtained results, we find that the electrical contribution of the Au NPs is a more dominant factor for enhancing cell efficiency when compared to the plasmonic effect.