Applicability of Pre-Plastic Deformation Method for Improving Mechanical Properties of Bulk Metallic Glasses.

Pre-plastic deformation (PPD) treatments on bulk metallic glasses (BMGs) have previously been shown to be helpful in producing multiple shear bands. In this work, the applicability of the PPD approach on BMGs with different Poisson's ratios was validated based on experimental and simulation observations. It was found that for BMGs with high Poisson's ratios (HBMGs, e.g., Zr56Co28Al16 and Zr46Cu46Al8), the PPD treatment can easily trigger a pair of large plastic deformation zones consisting of multiple shear bands. These PPD-treated HBMGs clearly display improved strength and compressive plasticity. On the other hand, the mechanical properties of BMGs with low Poisson's ratios (LBMG, e.g., Fe48Cr15Mo14Y2C15B6) become worse due to a few shear bands and micro-cracks in extremely small plastic deformation zones. Additionally, for the PPD-treated HBMGs with similar high Poisson's ratios, the Zr56Co28Al16 BMG exhibits much larger plasticity than the Zr46Cu46Al8 BMG. This phenomenon is mainly due to more defective icosahedral clusters in the Zr56Co28Al16 BMG, which can serve as nucleation sites for shear transformation zones (STZs) during subsequent deformation. The present study may provide a basis for understanding the plastic deformation mechanism of BMGs.

Relaxation and Strain-Hardening Relationships in Highly Rejuvenated Metallic Glasses.

One way to rejuvenate metallic glasses is to increase their free volume. Here, by randomly removing atoms from the glass matrix, free volume is homogeneously generated in metallic glasses, and glassy states with different degrees of rejuvenation are designed and further mechanically tested. We find that the free volume in the rejuvenated glasses can be annihilated under tensile or compressive deformation that consequently leads to structural relaxation and strain-hardening. Additionally, the deformation mechanism of highly rejuvenated metallic glasses during the uniaxial loading-unloading tensile tests is investigated, in order to provide a systematic understanding of the relaxation and strain-hardening relationship. The observed strain-hardening in the highly rejuvenated metallic glasses corresponds to stress-driven structural and residual stress relaxation during cycling deformation. Nevertheless, the rejuvenated metallic glasses relax to a more stable state but could not recover their initial as-cast state.

Second-harmonic generation of single-mode Laguerre-Gaussian beams with an improved quasi-phase-matching method.

In the second-harmonic generation processes involving Laguerre-Gaussian (LG) beams, the generated second-harmonic wave is generally composed of multiple modes with different radial quantum numbers. To generate single-mode second-harmonic LG beams, a type of improved quasi-phase-matching method is proposed. The Gouy phase shift has been considered in the optical superlattice designing and an adjustment phase item is introduced. By changing the structure parameters, each target mode can be phase-matched selectively, whose purity can reach up to 95%. The single LG mode generated from the optical superlattice can be modulated separately and used as the input signals in the mode division multiplexing system.

In-Vivo Toxicity Studies and In-Vitro Inactivation of SARS-CoV-2 by Povidone-iodine In-situ Gel Forming Formulations.

To curb the spread of SARS-CoV-2, the etiologic agent of the COVID-19 pandemic, we characterize the virucidal activity of long-acting Povidone Iodine (PVP-I) compositions developed using an in-situ gel forming technology. The PVP-I gel forming nasal spray (IVIEW-1503) and PVP-I gel forming ophthalmic eye drop (IVIEW-1201) rapidly inactivated SARS-CoV-2, inhibiting the viral infection of VERO76 cells. No toxicity was observed for the PVP-I formulations. Significant inactivation was noted with preincubation of the virus with these PVP-I formulations at the lowest concentrations tested. It has been demonstrated that both PVP-I formulations can inactivate SARS-CoV-2 virus efficiently in both a dose-dependent and a time-dependent manner. These results suggest IVIEW-1503 and IVIEW-1201 could be potential agents to reduce or prevent the transmission of the virus through the nasal cavity and the eye, respectively. Further studies are needed to clinically evaluate these formulations in early-stage COVID-19 patients.

Structure⁻Property Relationships in Shape Memory Metallic Glass Composites.

Metallic glass composites with shape memory crystals show enhanced plasticity and work-hardening capability. We investigate the influence of various critical structural aspects such as, the density of crystalline precipitates, their distribution and size, and the structural features and intrinsic properties of the phase on the deformation behavior of metallic amorphous Cu 64 Zr 36 composites with B2 CuZr inclusions using molecular dynamics simulations. We find that a low density of small B2 inclusions with spacing smaller than the critical shear band length controls the formation and distribution of plastic zones in the composite and hinders the formation of critical shear bands. When the free path for shearing allows the formation of mature shear bands a high volume fraction of large B2 precipitates is necessary to stabilize the shear flow and avoid runaway instability. Additionally, we also investigate the deformation mechanism of composites with pure copper crystals for comparison, in order to understand the superior mechanical properties of metallic glass composites with shape memory crystals in more detail. The complex and competing mechanisms of deformation occurring in shape memory metallic glass composites allow this class of materials to sustain large tensile deformation, even though only a low-volume fraction of crystalline inclusions is present.

Optimal design of selective catalyst reduction denitrification system using numerical simulation.

The performance of selective catalyst reduction systems highly depends on the degree of mixing between NH3 and NOx and the flow uniformity of velocity and concentration, which are sensitive to several parameters such as the installment of gate leafs, a hybrid grid, a straightener, and the ammonia injection method. In this work, computational fluid dynamics was applied to investigate these parameters in heat recovery steam generators. Performance of gate leafs and a new type of hybrid grid was considered. Analyses showed that gate leafs significantly improved the uniformity of velocity distribution and that the new type of hybrid grid improved the uniformity of concentration distribution. The velocity relative standard deviation decreased from 19.6% to 5.4%, and the concentration relative standard deviation decreased from 70% to 12.7%. Experiments also qualitatively confirmed the reliability of simulation results. Moreover, the hybrid grid was optimized with different structures. Results indicated that a 30° crossed angle could obtain a better mixing between NH3 and NOx with a slight decrease in pressure. In addition, an optimal injection method of the ammonia injection grid was designed, and it was helpful in conducting the field operation. The relationship between the thickness of the straightener and the incident angle at the entrance of catalyst layer was discussed.

Development of poly(N-isopropylacrylamide)/alginate copolymer hydrogel-grafted fabrics embedding of berberine nanosuspension for the infected wound treatment.

In the present study, a novel hydrogel-grafted fabrics embedding of berberine nanosuspension was developed for the treatment of infected wound. Hydrogel-grafted fabric was prepared by graft copolymerization of N-isopropylacrylamide and alginate using ceric ammonium nitrate as initiator. Berberine nanosuspension was prepared and embedded in the hydrogel-grafted fabrics to achieve sustained drug release. The prepared hydrogel-grafted fabrics embedding of berberine nanosuspension was characterized by FT-IR spectroscopy, scanning electron microscopy, and swelling degree studies. Fourier transform infrared spectroscopy revealed that berberine was embedded into the matrix of hydrogel-grafted fabrics, rather than on the surface. Scanning electron microscopy showed that a thin hydrogel layer was formed on the surface of nonwoven fibers. The swelling study showed that hydrogel-grafted fabric had water absorbing characteristic with reversible temperature sensitivity. The drug release study demonstrated that hydrogel-grafted fabrics can be used as a sustained drug delivery system of hydrophobic compounds. The berberine nanosuspension embedded hydrogel-grafted fabric was further investigated in an animal infected wound model and was found to be a very promising wound healing dressing for the treatment and healing of infected wounds.

Development and characterization of an orodispersible film containing drug nanoparticles.

In this study, a novel orodispersible film (ODF) containing drug nanoparticles was developed with the goal of transforming drug nanosuspensions into a solid dosage form and enhancing oral bioavailability of drugs with poor water solubility. Nanosuspensions were prepared by high pressure homogenization and then transformed into ODF containing drug nanoparticles by mixing with hydroxypropyl methylcellulose solution containing microcrystalline cellulose, low substituted hydroxypropylcellulose and PEG-400 followed by film casting and drying. Herpetrione, a novel and potent antiviral agent with poor water solubility that extracted from Herpetospermum caudigerum, was chosen as a model drug and studied systematically. The uniformity of dosage units of the preparation was acceptable according to the criteria of Japanese Pharmacopoeia 15. The ODF was disintegrated in water within 30s with reconstituted nanosuspensions particle size of 280 ± 11 nm, which was similar to that of drug nanosuspensions, indicating a good redispersibility of the fast dissolving film. Result of X-ray diffraction showed that HPE in the ODF was in the amorphous state. In the in vitro dissolution test, the ODF containing HPE nanoparticles showed an increased dissolution velocity markedly. In the pharmacokinetics study in rats, compared to HPE coarse suspensions, the ODF containing HPE nanoparticles exhibited significant increase in AUC0-24h, Cmax and decrease in Tmax, MRT. The result revealed that the ODF containing drug nanoparticles may provide a potential opportunity in transforming drug nanosuspensions into a solid dosage form as well as enhancing the dissolution rate and oral bioavailability of poorly water-soluble drugs.

Influence of physicochemical properties on the in vitro skin permeation of the enantiomers, racemate, and eutectics of ibuprofen for enhanced transdermal drug delivery.

Physicochemical properties of chiral ibuprofen are significant to formulation scientists because its enantiomers and eutectics possess lower melting points than its racemate. The influence of these properties on transdermal formulation development, especially the relative effect of lowered melting point, on skin permeation must be carefully assessed to provide the most efficacious formulation. Thermodynamic properties and crystalline structures of the enantiomers, eutectics, and racemate of chiral ibuprofen were investigated by differential scanning calorimetry and X-ray powder diffraction. The effect of melting point lowering on membrane permeation rates was mathematically modeled. Model was validated by in vitro skin permeation experiments using different preparations of racemic ibuprofen, enantiomer, and eutectic. Both enantiomer and eutectic formed a two-phase liquid system containing an emulsifiable aqueous phase and an oily phase in the presence of aqueous isopropyl alcohol (aIPA). The eutectic emulsion had the highest permeation rate, a 2.21-fold increase in flux compared with saturated aIPA solutions of the racemate with a 2.03-fold increase in flux. Results from the two-phase liquid system supported those from the mathematical models, albeit somewhat lower, and confirmed their use in predicting maximum flux utilizing thermodynamic data. Study data also supported the idea that eutectic formation, for ibuprofen and probably other chiral drugs, may be one of the best ways to develop topical formulations for improved percutaneous absorption to avoid the use of permeation enhancers or synthetically modifying chemical structure.

The preformulation stability studies of a proline prodrug of methotrexate.

In order to reduce toxicity of methotrexate and improve bioavailability, permeability, and explore other delivery routes, a proline prodrug of methotrexate was synthesized and preformulation stability studies were conducted under accelerated conditions to assess compound liability and possible conversion to the parent drug. Forced degradation studies showed that the prodrug will degrade in the presence of water, acid, and heat (70 °C), generating the parent compound methotrexate. It was also found that this conversion is temperature dependent. In addition, the prodrug is extremely light and oxidative labile. Therefore, future formulation studies should be light protected and stabilized by a suitable antioxidant. It was also found that the prodrug is stable in the HPLC diluent, consisting of water and acetonitrile; stored bench-top and protected from light for up to two weeks.

Recent advances of siRNA delivery by nanoparticles.

INTRODUCTION: The field of RNA interference technology has been researched extensively in recent years. However, the development of clinically suitable, safe and effective drug delivery vehicles is still required. AREAS COVERED: This paper reviews the recent advances of non-viral delivery of small interfering RNA (siRNA) by nanoparticles, including biodegradable nanoparticles, liposomes, polyplex, lipoplex and dendrimers. The characteristics, composition, preparation, applications and advantages of different nanoparticle delivery strategies are also discussed in detail, along with the recent progress of non-viral nanoparticle carrier systems for siRNA delivery in preclinical and clinical studies. EXPERT OPINION: Non-viral carrier systems, especially nanoparticles, have been investigated extensively for siRNA delivery, and may be utilized in clinical applications in the future. So far, a few preliminary clinical trials of nanoparticles have produced promising results. However, further research is still required to pave the way to successful clinical applications. The most important issues that need to be focused on include encapsulation efficiency, formulation stability of siRNA, degradation in circulation, endosomal escape and delivery efficiency, targeting, toxicity and off-target effects. Pharmacology and pharmacokinetic studies also present another great challenge for nanoparticle delivery systems, owing to the unique nature of siRNA oligonucleotides compared with small molecules.

Analytical methods for heavy metals in herbal medicines.

INTRODUCTION: It is estimated that about 70-80% of the world's population relies on non-conventional medicine, mainly of herbal origin. However, owing to the nature and sources of herbal medicines, they are sometimes contaminated with toxic heavy metals such as lead, arsenic, mercury and cadmium, which impose serious health risks to consumers. It is critical to analyse source materials for heavy metals in order to ensure that their concentrations meet the related standards or regulations limiting their concentrations in herbal medicines. In this review, different analytical methods for analysis of heavy metals in herbal medicines are discussed. OBJECTIVE: To provide a comprehensive review of the current state of the art in analytical methods used to detect heavy metals in herbal medicines. METHODOLOGY: We systematically searched and reviewed the research articles regarding analytical methods for heavy metals in herbal medicine from various databases, such as Medline/PubMed, ScienceDirect, SciFinder, Google Scholar, EBSCO, Gale InfoTrac, Ingenta, Ovid, ProQuest and ISI Web of Knowledge. RESULTS: In this review, we discuss in detail several commonly used and sensitive analytical techniques, including atomic absorption spectrometry, inductively coupled plasma optical emission spectrometry or mass spectrometry, X-ray fluorescence spectrometry, high-performance liquid chromatography, differential pulse polarography, neutron activation analysis and anodic stripping voltammetry. We also provide some application examples of these analytical techniques for heavy metals in herbal medicines.

Development of methotrexate proline prodrug to overcome resistance by MDA-MB-231 cells.

The resistance to methotrexate by a number of cancer cells such as breast cancer cell-line MDA-MB-231 due to poor permeability renders it less effective as an anticancer agent for these cells. Proline prodrug of methotrexate (Pro-MTX) was designed as a substrate of prolidase which is specific for imido bond of dipeptide containing proline and expected to penetrate MDA-MB-231 cells more efficiently. The prodrug was synthesized by solid-phase peptide synthesis method and examined as a substrate of pure prolidase as well as cell homogenate. The cytotoxicity against MDA-MB-231 and non-methotrexate resistant breast cancer cell line, MCF-7 was also examined by XTT assay. The results showed that Pro-MTX was a substrate of prolidase. It was also shown that the prodrug could be converted to parent drug methotrexate in Caco-2 and HeLa cell homogenate. When tested with Caco-2 and MCF-7 cells, Pro-MTX showed weaker cytotoxicity compared with methotrexate. But for methotrexate resistant MDA-MB-231 cells, Pro-MTX showed stronger activity than methotrexate. The results indicated that the proline prodrug of methotrexate may overcome the resistance of human breast cancer cells in culture.

Development of acetaminophen proline prodrug.

In this research work, proline ester prodrug of acetaminophen (Pro-APAP) was synthesized and evaluated for its stability in PBS buffer at various pH and Caco-2 cell homogenate. The Pro-APAP is more stable at lower pH than higher pH, with half-life of 120min in PBS buffer at pH 2.0, half-life of 65min at pH 5.0, and half life of 3.5min at pH 7.4, respectively. The half-life of Pro-APAP in Caco-2 cell homogenate is about 1min, much shorter than the half-life in PBS buffer at pH 7.4, indicating enzymes in the cell homogenate contribute to the hydrolysis of the ester bond. Carboxypeptidase A was incubated with Pro-APAP at pH 7.4 with half-life of 3.8min which is very close to the half life in buffer itself. This clearly indicates carboxypeptidase A is not one of the enzymes contributing to the hydrolysis of the prodrug. Physicochemical characteristics such as melting point and stability of newly synthesized prodrug were determined by MDSC technique.

Physicochemical studies of binary eutectic of ibuprofen and ketoprofen for enhanced transdermal drug delivery.

METHODS: The thermodynamic, eutectic, and crystalline properties of ibuprofen and ketoprofen binary mixtures were investigated using differential scanning calorimetry (DSC) and X-ray powder diffractometry (XRPD). RESULTS: The DSC studies showed that melting point (61 degrees C), enthalpy (11.3 kJ/mol), and entropy of fusion (33.7 J/K/mol) of the binary eutectic were significantly lower than those of the individual anti-inflammatory drugs (NSAIDs). Due to the melting-point depression and enhanced skin lipid solubility, the steady-state flux of ibuprofen and ketoprofen from preparations of the binary eutectic increased as compared to pure NSAIDs using shed snakeskin as a model membrane. The NSAID membrane flux values were calculated by flux ratio equations based on drug thermodynamic data, and compared to experimental values obtained from permeation studies. CONCLUSION: The proposed flux ratio equations correctly predicted flux increase.

The development and mechanism studies of cationic chitosan-modified biodegradable PLGA nanoparticles for efficient siRNA drug delivery.

PURPOSE: In order to improve siRNA delivery for possible clinical applications, we developed biodegradable chitosan-modified poly(D,L-lactide-co-glycolide) (CHT-PLGA) nanoparticles with positive surface charge, high siRNA loading, high transfection efficiency and low toxicity. METHODS: CHT-PLGA nanoparticles were prepared, and siRNA was loaded by emulsion evaporation method with poly(vinyl alcohol) (PVA) as emulsifier. siRNA loading efficiency, particle size, and Zeta potential of nanoparticles were measured. Gel retardation and protection assays were conducted to determine the loading and binding of siRNA in the formulation. Cell transfection was performed to study in vitro siRNA silencing efficiency. XTT assay was used to evaluate the cytotoxicity. RESULTS: It was found that the nanoparticle diameter and positive Zeta potential increase as the chitosan coating concentration increases. CHT-PLGA nanoparticles showed excellent siRNA binding ability and effective protection of oligos from RNase degradation. siRNA-loaded nanoparticles were successfully delivered into the HEK 293 T cell line, and the silencing of green fluorescence protein (GFP) expression was observed using fluorescent microscopy and flow cytometry. In addition, the cytotoxicity assay revealed that CHT-PLGA nanoparticles had relatively low cytotoxicity. CONCLUSION: This study suggests that biodegradable cationic CHT-PLGA nanoparticles possess great potential for efficient and safer siRNA delivery in future clinical applications.

The analysis of heavy metals in Chinese herbal medicine by flow injection-mercury hydride system and graphite furnace atomic absorption spectrometry.

INTRODUCTION: Simple and robust atomic absorption spectrometry (AAS) analytical methods were developed to determine the contents of arsenic (As), lead (Pb) and mercury (Hg) contained in Chinese herbal medicine products or Chinese proprietary medicine. OBJECTIVE: To develop AAS analytical methods to determine the contents of the toxic heavy metals in herbal medicine, and thus monitor them according to the regulated content limits to ensure the quality and safety of herbal products. METHODOLOGY: A flow injection-mercury hydride system technique was used for the quantitation of As and Hg, and a graphite furnace technique was used for the analysis of Pb. Limits of detection (LOD) for the three toxic heavy metals were found to be 0.3 ppb for As, 0.1 ppb for Pb and 0.5 ppb for Hg. Eight samples of 'Yin Qiao Jie Du' tablets available on the market were selected as the model herbal medicine for analysis. CONCLUSION: The developed analytical methods are sensitive enough to detect these heavy metals to meet regulated guidelines. No trace amounts of Hg were found in the test samples due to the fact that the Hg level is less than the LOD. However, variable amounts of As (135.0-5349.3 ppb) and Pb (22.5-968.3 ppb) were found in all products.

SiRNA drug delivery by biodegradable polymeric nanoparticles.

RNA interference (RNAi) is an emerging technology in which the introduction of double-stranded RNA (dsRNA) into a diverse range of organisms and cell types causes degradation of the complementary mRNA. It offers a broad spectrum of applications in both biological and medical research. Small interference RNA (siRNA) was recently explored for its therapeutical potential. However, the drug delivery of siRNA oligos is very novel and is in great need of future research. To this end, a biodegradable poly(D,L-lactide-co-glycolide) (PLGA) nanoparticle drug carrier system was prepared to load siRNA oligos with desired physicochemical properties. The nanoparticles were characterized by scanning electron microscopy and laser diffraction particle sizer. The delivery of siRNA into the targeted 293T cells was observed using fluorescent-labeled double-stranded Cy3-oligos. The model siRNA oligos, si-GFP-RNA, were also successfully loaded into PLGA nanoparticles and delivered in 293T cells. The gene silencing effect and the inhibition of GFP expression were investigated using fluorescent microscopy. Both positive and negative controls were used to compare with the new siRNA nanoparticle delivery system. It was found that nanoparticles offered both effective delivery of siRNA and prominent GFP gene silencing effect. Compared to conventional carrier systems, the new biodegradable polymeric nanoparticle system may also offer improved formulation stability, which is practically beneficial and may be used in the future clinical studies of siRNA therapeutics.

A high performance liquid chromatography method for the simultaneous determination of arctiin, chlorogenic acid and glycyrrhizin in a Chinese proprietary medicine.

A high performance liquid chromatography (HPLC) method was developed for the simultaneous determination of arctiin, chlorogenic acid and glycyrrhizin in the tablets of a Chinese proprietary medicine named, "Yin Qiao Jie Du Pian". The analysis was performed by a reverse phase gradient elution, using an aqueous mobile phase (containing 0.4% acetic acid and 4.5% tetrahydrofuran) modified by acetonitrile and detection made simultaneously at three wavelengths. The method was validated for specificity, accuracy, precision and limits of detection and quantification. Tablets of seven commercial brands were analyzed and found to contain different amounts of the three bioactive markers. This raised the question of the quality and the efficacy of the products. The method developed can be used for the quality control of "Yin Qiao Jie Du" tablets.

The binary eutectic of NSAIDS and two-phase liquid system for enhanced membrane permeation.

The eutectic properties of binary mixtures of some nonsteroidal anti-inflammatory drugs (NSAIDs) with ibuprofen were studied using differential scanning calorimetry (DSC) and phase equilibrium diagrams. The melting points of selected NSAIDs were significantly depressed due to binary eutectic formation with ibuprofen. Ketoprofen and ibuprofen were selected to study the effect of eutectic formation on membrane permeation using Franz diffusion cells and snake skin as the model membrane. The presence of aqueous isopropyl alcohol (IPA) was necessary to completely transform the solid drugs into an oily state at ambient temperature. As much as the 99.6% of ibuprofen and the 88.8% of ketoprofen added were found in the oily phase of the two-phase liquid system formed when aqueous IPA was added to the eutectic mixture. Due to the high drug concentration in the oily phase, and maximum thermodynamic activity, the two-phase liquid system showed enhanced membrane permeation rates of ibuprofen (37.5 microg/cm2/hr) and ketoprofen (33.4 microg/cm2/hr) compared to other reference preparations used.