Fine tuning of the net charge alternation of polyzwitterion surfaced lipid nanoparticles to enhance cellular uptake and membrane fusion potential.

Lipid nanoparticles (LNPs) coated with functional and biocompatible polymers have been widely used as carriers to deliver oligonucleotide and messenger RNA therapeutics to treat diseases. Poly(ethylene glycol) (PEG) is a representative material used for the surface coating, but the PEG surface-coated LNPs often have reduced cellular uptake efficiency and pharmacological activity. Here, we demonstrate the effect of pH-responsive ethylenediamine-based polycarboxybetaines with different molecular weights as an alternative structural component to PEG for the coating of LNPs. We found that appropriate tuning of the molecular weight around polycarboxybetaine-modified LNP, which incorporated small interfering RNA, could enhance the cellular uptake and membrane fusion potential in cancerous pH condition, thereby facilitating the gene silencing effect. This study demonstrates the importance of the design and molecular length of polymers on the LNP surface to provide effective drug delivery to cancer cells.

The study presents the unique characteristics of small interfering RNA (siRNA)-loaded lipid nanoparticles (LNPs) with different lengths of PGlu(DET-Car), revealing the length of PGlu(DET-Car) critically affects the formation of a stable LNP, the cellular uptake, membrane fusion, and gene silencing abilities.

Cancerous pH-responsive polycarboxybetaine-coated lipid nanoparticle for smart delivery of siRNA against subcutaneous tumor model in mice.

Lipid nanoparticles (LNPs) have been commonly used as a vehicle for nucleic acids, such as small interfering RNA (siRNA); the surface modification of LNPs is one of the determinants of their delivery efficiency especially in systemic administration. However, the applications of siRNA-encapsulated LNPs are limited due to a lack effective systems to deliver to solid tumors. Here, we report a smart surface modification using a charge-switchable ethylenediamine-based polycarboxybetaine for enhancing tumor accumulation via interaction with anionic tumorous tissue constituents due to selective switching to cationic charge in response to cancerous acidic pH. Our polycarboxybetaine-modified LNP could enhance cellular uptake in cancerous pH, resulting in facilitated endosomal escape and gene knockdown efficiency. After systemic administration, the polycarboxybetaine-modified LNP accomplished high tumor accumulation in SKOV3-luc and CT 26 subcutaneous tumor models. The siPLK-1-encapsulated LNP thereby accomplished significant tumor growth inhibition. This study demonstrates a promising potential of the pH-responsive polycarboxybetaine as a material for modifying the surface of LNPs for efficient nucleic acid delivery.

Intensity fluctuations in ground-to-satellite laser beam transmission induced by atmospheric turbulence: reconsideration of strong fluctuation.

This paper reports beam wave intensity fluctuations in uplink (ground-to-satellite) laser beam transmission caused by atmospheric turbulence. Intensity fluctuation in the strong region was apparently induced by uplink measurement in previous experiments. Statistical values of the uplink fluctuation were estimated by numerical calculation using moment equation analysis with thin phase screen approximation. The beam profile of the uplink, the scintillation index, and the covariance of the uplink intensity fluctuation were calculated using models of the refractive index structure constant. The generation of strong intensity variation was explained as the result of a speckle pattern on the receiving plane at the satellite produced by atmospheric turbulence when scanned along with trajectory of the satellite.

Prediction of permeable thin absorbers using the finite-difference time-domain method.

Permeable thin materials can play a role similar to porous absorbents, providing high sound absorption at mid- and high-frequencies. In addition, since they can be made from various materials such as cotton, chemical fibers, and metal fibers, they can be hygienic, durable, and easy to recycle. Their absorption characteristics are often discussed with analytical approaches, and a few studies have even applied the boundary element method and the finite element method to predict the practical effects of permeable thin absorbers. However, to the best of the authors' knowledge, the finite-difference time-domain (FDTD) method has yet to be used. Herein a formulation to deal with a permeable thin absorber as a permeable boundary in the FDTD method is proposed and the stability conditions for a permeable boundary are derived considering the state transition equations. The proposed formulation is validated by comparing the numerical and analytical results, which agree well.

Numerical analyses of the sound absorption of cylindrical microperforated panel space absorbers with cores.

Microperforated panels (MPPs) are next-generation absorption materials because they can provide wideband sound absorption without fibrous materials and can be composed of diverse materials to meet global environmental demands. The fundamental absorbing mechanism is Helmholtz-resonance absorption due to perforations and an air cavity. MPPs are typically backed by rigid flat walls, but to reduce the restrictions on the MPP absorber properties, one of the authors has proposed MPP space sound absorbers without backing structures, including three-dimensional cylindrical microperforated panel space absorbers (CMSAs). Advantages of MPPs without backing structures are design flexibility and ease of use. Besides, the absorption characteristics of a CMSA with a core, which has a rigid cylindrical core inside the CMSA, have been experimentally tested, but a method to predict the absorption characteristics is necessary to design CMSAs with cores. Herein the two-dimensional combined Helmholtz integral formulation method is employed, and its prediction accuracy is evaluated by comparing the measured and predicted absorption characteristics of a CMSA with a core. Furthermore, a parametric study with regard to the core size is carried out to investigate the transition of the absorbing mechanism.

pH-responsive polyzwitterion covered nanocarriers for DNA delivery.

The success of gene therapy relies on gene nanocarriers to achieve therapeutic effects in vivo. Surface shielding of poly(ethylene glycol) (PEG), known as PEGylation, onto gene delivery carriers is a predominant strategy for extending blood circulation and improving therapeutic outcomes in vivo. Nevertheless, PEGylation frequently compromises the transfection efficiency by decreasing the interactions with the cellular membrane of the targeted cells, thereby preventing the cellular uptake and the subsequent endosomal escape. Herein, we developed a stepwise pH-responsive polyplex micelle for the plasmid DNA delivery with the surface covered by ethylenediamine-based polycarboxybetaines. This polyplex micelle switched its surface charge from neutral at pH 7.4 to positive at tumorous and endo-/lysosomal pH (i.e., pH 6.5 and 5.5, respectively), thus enhancing the cellular uptake and facilitating the endosomal escape toward efficient gene transfection. Additionally, the polyplex micelle demonstrated prolonged blood circulation as well as enhanced tumor accumulation, leading to highly effective tumor growth suppression by delivering an antiangiogenic gene. These results suggest the usefulness of a pH-responsive charge-switchable shell polymer on the surface of the polyplex micelle for the efficient nucleic acid delivery.

Changeable net charge on nanoparticles facilitates intratumor accumulation and penetration.

The Enhanced Permeability and Retention (EPR) effect is a golden strategy for the nanoparticle (NP)-based targeting of solid tumors, and the surface property of NPs might be a determinant on their targeting efficiency. Poly(ethylene glycol) (PEG) is commonly used as a shell material; however, it has been pointed out that PEG-coated NPs may exhibit accumulation near tumor vasculature rather than having homogenous intratumor distribution. The PEG shell plays a pivotal role on prolonged blood circulation of NPs but potentially impairs the intratumor retention of NPs. In this study, we report on a shell material to enhance tumor-targeted delivery of NPs by maximizing the EPR effect: polyzwitterion based on ethylenediamine-based carboxybetaine [PGlu(DET-Car)], which shows the changeable net charge responding to surrounding pH. The net charge of PGlu(DET-Car), is neutral at physiological pH 7.4, allowing it to exhibit a stealth property during the blood circulation; however, it becomes cationic for tissue-interactive performance under tumorous acidic conditions owing to the stepwise protonation behavior of ethylenediamine. Indeed, the PGlu(DET-Car)-coated NPs (i.e., gold NPs in the present study) exhibited prolonged blood circulation and remarkably enhanced tumor accumulation and retention than PEG-coated NPs, achieving 32.1% of injected dose/g of tissue, which was 4.2 times larger relative to PEG-coated NPs. Interestingly, a considerable portion of PGlu(DET-Car)-coated NPs clearly penetrated into deeper tumor sites and realized the effective accumulation in hypoxic regions, probably because the cationic net charge of PGlu(DET-Car) is augmented in more acidic hypoxic regions. This study suggests that the changeable net charge on the NP surface in response to tumorous acidic conditions is a promising strategy for tumor-targeted delivery based on the EPR effect.

Polymeric modification of gemcitabine via cyclic acetal linkage for enhanced anticancer potency with negligible side effects.

Gemcitabine (GEM) is a powerful anticancer drug for various cancers. However, the anticancer efficacy and the side effects should be addressed for effective therapeutics. To this end, we created a GEM-conjugated polymer (P-GEM) based on cyclic acetal linkage as a delivery carrier of GEM. The obtained P-GEM stably conjugated GEM at physiological pH (i.e., bloodstream), but released GEM in response to acidic environments such as endosome/lysosome. After systemic administration of P-GEM for mice bearing subcutaneous tumors, it achieved prolonged blood circulation and enhanced tumor accumulation relative to free GEM system. In addition, the polymer-drug conjugate structure of P-GEM realized effective distribution in the tumor tissues toward the induction of apoptosis in most areas of the tumor sites. Of note, the molecular design of P-GEM achieved minimal accumulation in normal tissues, resulting in negligible GEM-derived adverse effects (e.g., gastrointestinal toxicity and hematotoxicity). Ultimately, even four times smaller dose of P-GEM on a GEM basis realized comparable/higher tumor growth suppression effect for two distinct pancreatic tumor models, compared to free GEM system. The obtained results suggest the huge potential of the present design of GEM-conjugated polymer for anticancer therapeutics.

Structure and photoactivity of titania derived from nanotubes and nanofibers.

Photoactivity under UV irradiation for the decomposition of methylene blue in water and for the oxidation of NO gas was studied on titania powders derived from titanate nanotube (TNT) and nanofiber (TNF) by annealing at high temperatures, comparing with granular titania (ST-01). Rate constant for methylene blue decomposition k(MB) increased with increasing annealing temperature above 300 degrees C after the conversion from titanate to tinania. It tended to decrease above 700 degrees C, mainly due to the phase transformation from anatase to rutile. The dependences of k(MB) on full width at half maximum intensity (FWHM) were common for three samples, a sharp maximum at around 0.4 degrees in FWHM, but TNF-derived sample gave much higher maximum than ST-01. Change in fraction of oxidized NO with annealing temperature showed a plateau at around 50% and then decreased abruptly by high temperature annealing. Starting from TNT and TNF has an advantage to form fine particles by annealing above 300 degrees C, giving high photoactivity due to high crystallinity and high adsorptivity particularly for methylene blue.

Sound transmission through a microperforated-panel structure with subdivided air cavities.

The absorption characteristics of a microperforated-panel (MPP) absorber have been widely investigated, and MPPs are recognized as a next-generation absorbing material due to their fiber-free nature and attractive appearance. Herein, further possibilities of MPPs are investigated theoretically from a sound transmission viewpoint. Employing an analytical model composed of a typical MPP and a back wall with an infinite extent, transmission loss through the structure is obtained. Although MPP structures generally have great potential for sound absorption, an improvement in the transmission loss at midfrequencies, which is important for architectural sound insulation, is not sufficient when using a backing cavity alone. Hence, to improve transmission loss at midfrequencies, an air-cavity-subdivision technique is applied to MPP structures. By subdividing the air cavity with partitions, each cell can create a local one-dimensional sound field as well as lead to a normal incidence into the apertures, which is the most effective condition for Helmholtz-type resonance absorption. Moreover, by providing the same motion as the back wall to the MPP, the sound-insulation performance can be further improved at midfrequencies.

Effects of an air-layer-subdivision technique on the sound transmission through a single plate.

Many studies on the sound transmission through a single plate have been carried out theoretically and experimentally. The transmission-loss characteristics, in general, follow mass law. Therefore, increasing mass of a plate is a fundamental measure to improve the insulation performance. This method, however, has limitations and might not be a reasonable alternative in current standards. Furthermore, the transmission loss at the critical frequency of coincidence is deteriorated significantly even if the mass is rather large. In this paper, the effect of the air-layer-subdivision technique is studied in detail from the viewpoint of the sound transmission problem of a single plate. An analytical model of an infinite single plate with a subdivided layer is considered and the improvement of the transmission loss is estimated. The limitations of the technique are clarified with some parametric studies. In order to validate the predictions, an experiment was carried out. The transmission loss of a glass board with the air layer subdivided by acryl partitions was measured in the experiment. They were in good agreement with the theoretical ones near and above the coincidence.

Enhancing the effects of exfoliated carbon nanofibers using bone morphogenetic protein in a rat spinal fusion model.

Exfoliated carbon nanofibers (ExCNFs) are expected to serve as excellent scaffolds for promoting and guiding bone-tissue regeneration. We aimed to enhance the effects of ExCNFs using bone morphogenetic proteins (BMPs) and examined their feasibility and safety in clinical applications using a rat spinal fusion model. Group I (n = 15) animals were implanted with the control carrier; Group II (n = 16) animals were implanted with carrier containing 1 µg ExCNFs; Group III (n = 16) animals were implanted with carrier containing 1 µg recombinant human (rh) BMP-2; and Group IV (n = 17) animals were implanted with carrier containing 1 µg rhBMP-2 and 1 µg ExCNFs. The rats were euthanized after 4 or 8 weeks and their spines were explanted and assessed by manual palpation, radiographs, and high-resolution microcomputerized tomography (micro-CT); the spines were also subjected to histological analysis. The fusion rates in Group IV (25.0%: 4-week, 45.5%: 8-week) were considerably higher than in Groups I (0%: 4-week, 0%: 8-week), II (0%: 4-week, 15.0%: 8-week), and III (16.7%: 4-week, 30.0%: 8-week). These results demonstrated the enhancement of ExCNF bone fusion effects by BMP in a rat spinal fusion model. Our results suggest that the enhancement of ExCNFs effects by BMP makes this combination a possible attractive therapy for spinal fusion surgeries. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:2892-2900, 2018.

Application of carbon-coated TiO2 for decomposition of methylene blue in a photocatalytic membrane reactor.

An application of carbon-coated TiO(2) for decomposition of methylene blue (MB) in a photocatalytic membrane reactor (PMR), coupling photocatalysis and direct contact membrane distillation (DCMD) was investigated. Moreover, photodegradation of a model pollutant in a batch reactor without membrane distillation (MD) was also examined. Carbon-modified TiO(2) catalysts containing different amount of carbon and commercially available TiO(2) (ST-01) were used in this study. The carbon-coated catalyst prepared from a mixture of ST-01 and polyvinyl alcohol in the mass ratio of 70/30 was the most effective in degradation of MB from all of the photocatalysts applied. Photodecomposition of MB on the recovered photocatalysts was lower than on the fresh ones. The photodegradation of MB in the PMR was slower than in the batch reactor, what probably resulted from shorter time of exposure of the catalyst particles to UV irradiation. The MD process could be successfully applied for separation of photocatalyst and by-products from the feed solution.

Effect of the carbon coating in Fe-C-TiO(2) photocatalyst on phenol decomposition under UV irradiation via photo-Fenton process.

Fe-C-TiO(2) photocatalysts which contained the residue carbon (0.2-3.3 mass%) were prepared from a mixture of TiO(2) and FeC(2)O(4) through the heating at 673-1173 K in Ar. These photocatalysts did not show a high adsorption of phenol, but they were active in photo-Fenton reactions during decomposition of phenol under UV irradiation with addition of H(2)O(2). It was proved that Fe(2+) governed the photoactivity of Fe-C-TiO(2) photocatalysts, it decreased with heat-treatment temperature above 773 K. For comparison, Fe-TiO(2) photocatalyst was prepared by heating TiO(2) and FeC(2)O(4) at 823 K in air for 3h. Phenol decomposition was going much slower on Fe-TiO(2) photocatalyst in comparison with Fe-C-TiO(2), of which mechanism was different, on the former phenol was decomposed by the radical reaction, on the latter through a complex reaction with iron and intermediates of phenol decomposition. Therefore carbon-coating TiO(2) was found to be advantageous for mounting iron and its application for the phenol decomposition via photo-Fenton process.

Enhancement of the effects of exfoliated carbon nanofibers by bone morphogenetic protein in a rat femoral fracture model.

Exfoliated carbon nanofibers (ExCNFs) are expected to serve as excellent scaffolds for promoting and guiding bone-tissue regeneration. We aimed to enhance the effects of ExCNFs with bone morphogenetic proteins (BMPs) and examine their feasibility and safety in clinical applications using a rat femoral fracture model. Group I (n = 16) animals were implanted with control MedGEL. Group II (n = 17) animals were implanted with MedGEL containing ExCNFs. Group III (n = 15) animals were implanted with MedGEL containing 1 µg rhBMP-2. Group IV (n = 15) animals were implanted with MedGEL containing 1 µg rhBMP-2 and ExCNFs. The rats were euthanized after 6 weeks, and their fractured femurs were explanted and assessed by manual palpation, radiographs, and high-resolution microcomputerized tomography (micro-CT); the femurs were also subjected to biomechanical and histological analysis. The fusion rates in Group IV (73.3%) were considerably higher than those in Groups I (25.0%), II (52.9%), and III (46.7%). The results demonstrated the enhancement of the bone repair effects of ExCNFs by BMP in a rat femoral fracture model. Our results suggest that the enhancement of the effects of ExCNFs by BMP makes the combination a possible attractive therapy for various orthopedic surgeries.

Porous carbon material containing CaO for acidic gas capture: preparation and properties.

A one-step process for the preparation of CaO-containing porous carbons is described. Mixtures of poly(ethylene terephthalate) with natural limestone were pyrolyzed and thus hybrid sorbents could be easily obtained. The polymeric material and the mineral served as a carbon precursor and CaO delivering agent, respectively. We discuss effects of the preparation conditions and the relative amounts of the raw materials used for the preparations on the porosity of the hybrid products. The micropore areas and volumes of the obtained products tended to decrease with increasing CaO contents. Increase in the preparation temperature entailed a decrease in the micropore volume, whereas the mesopore volume increased. The pore creation mechanism is proposed on the basis of thermogravimetric and temperature-programmed desorption measurements. The prepared CaO-containing porous carbons efficiently captured SO2 and CO2 from air. Washing out of CaO from the hybrid materials was confirmed as a suitable method to obtain highly porous carbon materials.

Intensity fluctuations in laser links between the ground and a satellite.

Laser-beam-intensity fluctuations between an uplink (ground to satellite) and a downlink (satellite to ground) are described. The dependence of the beam radius on log-intensity variance in the uplink and the dependence of receiving-aperture diameter on the log-intensity variance in the downlink using a known theory were calculated. Statistical analysis of the experimental data on the laser links was performed, and high correlation coefficients of 0.94 between the normalized intensity variances of the uplink and those of the stellar scintillation were obtained. The beam-pointing error in the satelliteborne laser transmitter chiefly caused fluctuations in the downlink.

Wave-front tilt sensor with two quadrant detectors and its application to a laser beam pointing system.

A method that uses two quadrant detectors (QDs) for sensing wave-front tilt is described. The detectors are set at the front and back of the focal plane of the focusing optics. When the intensity distribution at the aperture of a telescope is not uniform because of atmospheric turbulence, the wave-front tilt can be measured more accurately with our two-QD method than with a conventional single-focal-plane QD. We proved this method to be effective by using it for fixed-star observation. Application of the method to a ground-to-satellite laser beam pointing system showed that it increases the intensity of the laser beam that is transmitted to a satellite.

The most profitable use of flow visualization in the elimination of thrombus from a monopivot magnetic suspension blood pump.

The purpose of this study was to eliminate fluid dynamic causes of thrombus formation for the monopivot magnetic suspension centrifugal pump under development with the aid of flow visualization as an indirect measurement tool for animal experiments. The formation of thrombus observed in early animal experiments was successfully overcome by combining the multiple washout holes at the center into a single hole, optimizing the hole diameter, and eliminating the pivot gap. Flow visualization was used to optimize the washout hole diameter influencing the flow around the pivot. In animal experiments flow visualization showed that the contours of thrombus corresponded to shear rates of 300 s(-1) or 1300-1700 s(-1). It was found that flow visualization is a useful technique to predict locations where low shear thrombi form and to optimize the pump design in the development stage.