Co-spray dried inhalable composite powders of ciprofloxacin and alginate oligosaccharide as anti-biofilm therapy.

The treatment of chronic respiratory infections caused by biofilm formation are extremely challenging owing to poor drug penetration into the complex biofilm structure and high drug resistance. Local delivery of an antibiotic together with a non-antibiotic adjuvant to the lungs could often enhance the therapeutic responses by targeting different bacterial growth pathways and minimizing drug resistance. In this study, we designed new inhalable dry powders containing ciprofloxacin (CIP) and OligoG (Oli, a low-molecular-weight alginate oligosaccharide impairing the mucoid biofilms by interacting with their cationic ions) to combat respiratory bacterial biofilm infections. The resulting powders were characterized with respect to their morphology, solid-state property, surface chemistry, moisture sorption behavior, and dissolution rate. The aerosol performance and storage stability of the dry powders were also evaluated. The results showed that inhalable dry powders composed of CIP and Oli could be readily accomplished via the wet milling and spray drying process. Upon the storage under 20 ± 2 °C/20 ± 2 % relative humidity (RH) for one month, there was no significant change in the in vitro aerosol performances of the dry powders. In contrast, the dry powders became non-inhalable following the storage at 20 ± 2 °C/53 ± 2 % RH for one month due to the hygroscopic nature of Oli, which could be largely prevented by incorporation of leucine. Collectively, this study suggests that the newly developed co-spray-dried powders composed of CIP and Oli might represent a promising and alternative treatment strategy against respiratory bacterial biofilm infections.

Identification and Localization of Labile Molecules in Broccoli Cell by CLA-ICP-MS and Single-Cell Nanospray HRMS.

Although molecular analysis and imaging by mass spectrometry are emerging as tools to identify metabolites and determine their distribution in cells and tissues, it is difficult to directly analyze the labile molecules at the single-cell level. Glucosinolate (GL) is a plant-active substance with much attention as a chemical defense mechanism known as a "mustard oil bomb" in broccoli. When tissue is damaged, these substances undergo rapid degradation, making them unsuitable for conventional mass spectrometry (MS), particularly for surface MS imaging analysis methods that necessitate intricate preprocessing. Herein, a strategy combining cryogenic laser ablation inductively coupled mass spectrometry (CLA-ICP-MS) and capillary microsampling nanospray high-resolution mass spectrometry (HRMS) was developed. The sulfur-rich microzone in tissue which was thought as a suspect GL-rich cell population was located via CLA-ICP-MS. Three GLs in single cells were accurately identified by nanospray HRMS with a hydrogen/deuterium exchange reaction. Subsequently, cell-by-cell imaging by nanospray HRMS showed that the GL-rich cells were below the stalk surface by approximately 30 µm. This proposed strategy can also be applied to rapidly identify labile compounds and localize molecule-rich cells in tissues.

In Vitro and In Vivo Evaluation of Inhalable Ciprofloxacin Sustained Release Formulations.

Respiratory antibiotics delivery has been appreciated for its high local concentration at the infection sites. Certain formulation strategies are required to improve pulmonary drug exposure and to achieve effective antimicrobial activity, especially for highly permeable antibiotics. This study aimed to investigate lung exposure to various inhalable ciprofloxacin (CIP) formulations with different drug release rates in a rat model. Four formulations were prepared, i.e., CIP-loaded PLGA micro-particles (CHPM), CIP microcrystalline dry powder (CMDP), CIP nanocrystalline dry powder (CNDP), and CIP spray-dried powder (CHDP), which served as a reference. The physicochemical properties, drug dissolution rate, and aerosolization performance of these powders were characterized in vitro. Pharmacokinetic profiles were evaluated in rats. All formulations were suitable for inhalation (mass median aerodynamic diameter < 5 µm). CIP in CHPM and CHDP was amorphous, whereas the drug in CMDP and CNDP remained predominantly crystalline. CHDP exhibited the fastest drug release rate, while CMDP and CNDP exhibited much slower drug release. In addition, CMDP and CNDP exhibited significantly higher in vivo lung exposure to CIP compared with CHDP and CHPM. This study suggests that lung exposure to inhaled drugs with high permeability is governed by drug release rate, implying that lung exposure of inhaled antibiotics could be improved by a sustained-release formulation strategy.

Oligomer nanoparticle release from polylactic acid plastics catalysed by gut enzymes triggers acute inflammation.

The health risks of exposure to 'eco-friendly' biodegradable plastics of anthropogenic origin and their effects on the gastrointestinal tract are largely unknown. Here we demonstrate that the enzymatic hydrolysis of polylactic acid microplastics generated nanoplastic particles by competing for triglyceride-degrading lipase during gastrointestinal processes. Nanoparticle oligomers were formed by hydrophobically driven self-aggregation. In a mouse model, polylactic acid oligomers and their nanoparticles bioaccumulated in the liver, intestine and brain. Hydrolysed oligomers caused intestinal damage and acute inflammation. A large-scale pharmacophore model revealed that oligomers interacted with matrix metallopeptidase 12. Mechanistically, high binding affinity (Kd = 13.3 µmol l-1) of oligomers to the catalytic zinc-ion finger domain led to matrix metallopeptidase 12 inactivation, which might mediate the adverse bowel inflammatory effects after exposure to polylactic acid oligomers. Biodegradable plastics are considered to be a solution to address environmental plastic pollution. Thus, understanding the gastrointestinal fates and toxicities of bioplastics will provide insights into potential health risks.

Combination and nanotechnology based pharmaceutical strategies for combating respiratory bacterial biofilm infections.

Respiratory infections are one of the major global health problems. Among them, chronic respiratory infections caused by biofilm formation are difficult to treat because of both drug tolerance and poor drug penetration into the complex biofilm structure. A major part of the current research on combating respiratory biofilm infections have been focused on destroying the matrix of extracellular polymeric substance and eDNA of the biofilm or promoting the penetration of antibiotics through the extracellular polymeric substance via delivery technologies in order to kill the bacteria inside. There are also experimental data showing that certain inhaled antibiotics with simple formulations can effectively penetrate EPS to kill surficially located bacteria and centrally located dormant bacteria or persisters. This article aims to review recent advances in the pharmaceutical strategies for combating respiratory biofilm infections with a focus on nanotechnology-based drug delivery approaches. The formation and characteristics of bacterial biofilm infections in the airway mucus are presented, which is followed by a brief review on the current clinical approaches to treat respiratory biofilm infections by surgical removal and antimicrobial therapy, and also the emerging clinical treatment approaches. The current combination of antibiotics and non-antibiotic adjuvants to combat respiratory biofilm infections are also discussed.

Determination of As species distribution and variation with time in extracted groundwater samples by on-site species separation method.

It is challenging to dependably keep the native distribution of arsenic (As) species before sample analysis in the laboratory. The on-site separation method can avoid sample contamination and species change in the process of sample collection and transportation from field to laboratory. In this study, As species distribution and variation of the extracted groundwater was first analyzed by an on-site species separation method in Jianghan Plain, China. Our study illustrated that: 1) high-As groundwater generally existed under mildly reducing conditions (Eh < 200 mV), weak alkaline conditions (pH < 7.2), elevated concentrations of dissolved Fe(II) and S(-II), and high proportions of As (III); 2) As species in the groundwater changed dramatically at room temperature in 36 hours post extraction (HPE). Fe-sulfide and Fe oxides minerals, which adsorbed As (V), were the main reasons influencing the As species concentration; 3) Acidification and strong complexing agents cannot preserve As species effectively. The average proportion of As (III) in the wells, where groundwater samples from the depth of 25 m exceed 10 µg L-1 As, can be reduced by 61% and 63% after HCl and EDTA were added, respectively. Accurate assessment of concentrations and distribution variation of As species in groundwater can guide the removal of As and the safe use of water resources, especially in drought areas relying on drinking well water.

Hydrogen/Deuterium Exchange Aiding Metabolite Identification in Single-Cell Nanospray High-Resolution Mass Spectrometry Analysis.

The identification of metabolites in single-cell or small-volume tissue samples using single-cell mass spectrometry (MS) is challenging. In this study, hydrogen/deuterium (H/D) exchange was combined with microsampling nanospray high-resolution mass spectrometry (HRMS) to improve the efficiency and confidence level of metabolite identification in a single cell using commercial software. A nanospray ion source showed an improved reaction depth of 8% for H/D exchange compared with an electrospray ion source. In total, 273 metabolites were identified in Allium cepa L. single cells by searching commercial databases. Generally, more than one candidate is given for a precursor ion by MS or tandem MS (MS2) databases such as ChemSpider, MetDNA, MassBank, and mzCloud. With the help of the H/D exchange technique, the number of candidates decreased and reduction of the search space by a factor of 8 was achieved. In addition, two enzymolysis products of isoalliin, the transient intermediate and its isomer, were tracked at the single-cell level using the proposed method.

Pharmaceutical strategies to extend pulmonary exposure of inhaled medicines.

Pulmonary administration route has been extensively exploited for the treatment of local lung diseases such as asthma, chronic obstructive pulmonary diseases and respiratory infections, and systemic diseases such as diabetes. Most inhaled medicines could be cleared rapidly from the lungs and their therapeutic effects are transit. The inhaled medicines with extended pulmonary exposure may not only improve the patient compliance by reducing the frequency of drug administration, but also enhance the clinical benefits to the patients with improved therapeutic outcomes. This article systematically reviews the physical and chemical strategies to extend the pulmonary exposure of the inhaled medicines. It starts with an introduction of various physiological and pathophysiological barriers for designing inhaled medicines with extended lung exposure, which is followed by recent advances in various strategies to overcome these barriers. Finally, the applications of the inhaled medicines with extended lung exposure for the treatment of various diseases and the safety concerns associated to various strategies to extend the pulmonary exposure of the inhaled medicines are summarized.

In vitro - in vivo - in silico approach in the development of inhaled drug products: Nanocrystal-based formulations with budesonide as a model drug.

This study aims to understand the absorption patterns of three different kinds of inhaled formulations via in silico modeling using budesonide (BUD) as a model drug. The formulations investigated in this study are: (i) commercially available micronized BUD mixed with lactose (BUD-PT), (ii) BUD nanocrystal suspension (BUD-NC), (iii) BUD nanocrystals embedded hyaluronic acid microparticles (BUD-NEM). The deposition patterns of the three inhaled formulations in the rats' lungs were determined in vivo and in silico predicted, which were used as inputs in GastroPlus™ software to predict drug absorption following aerosolization of the tested formulations. BUD pharmacokinetics, estimated based on intravenous data in rats, was used to establish a drug-specific in silico absorption model. The BUD-specific in silico model revealed that drug pulmonary solubility and absorption rate constant were the key factors affecting pulmonary absorption of BUD-NC and BUD-NEM, respectively. In the case of BUD-PT, the in silico model revealed significant gastrointestinal absorption of BUD, which could be overlooked by traditional in vivo experimental observation. This study demonstrated that in vitro-in vivo-in silico approach was able to identify the key factors that influence the absorption of different inhaled formulations, which may facilitate the development of orally inhaled formulations with different drug release/absorption rates.

Analysis of rice and wheat flour by particle nebulization ICP-MS.

Analysis of toxic elements in food samples (e.g., rice and wheat) is very important for human health. A direct nebulization of solid particles for inductively coupled plasma (ICP) ionization and subsequent analysis of toxic elements (i.e., As, Cd, Hg, and Pb) by mass spectrometry (MS) was developed. Dried and well-ground food particles (mean size of 0.9-1.0 µm) were stably dispersed in 0.5% polyethylene-imine (PEI) and the particle slurries were analyzed by ICP-MS using aqueous standard calibration. The transportation and ionization behaviors of particles with different particle sizes in ICP-MS were compared with those of aqueous standards containing equivalent concentrations of the analyte. The results indicated that the upper limits of particle sizes for the efficient transportation and complete ionization were 7.5-8.0 µm and 3.3-3.5 µm, respectively. Satisfactory recovery (94-107%), and precision (0.4-6.5%, RSD, n = 3) were verified by analyzing a series of rice and wheat standard reference materials (SRMs). The limits of quantitation (LOQs, 1.1 ng g-1 (Hg) to 3.5 ng g-1 (As)) are compared with the traditional microwave-assisted acid digestion ICP-MS method, however, the analysis throughput of the proposed method is improved by more than 10 times.

Barrier layer induced channeling effect of As ion implantation in HgCdTe and its influences on electrical properties of p-n junctions.

The HgCdTe layers (xCd∼0.285 and 0.225) were grown by molecular beam epitaxy and liquid phase epitaxy, respectively, followed by the deposition of CdTe and ZnS films as barrier layers by thermal evaporation. Then, the p-on-n photodiodes were fabricated by AS ion implantation, Hg overpressure annealing, passivation, and metallization. The secondary ion mass spectrometry and transmission electron microscopy results indicate that the evaporated CdTe layer with a column structure induces the channeling effect of As ion implantation causing the device performance degradation. This effect could be suppressed by depositing a CdTe film with a layered structure through E-beam evaporation. Finally, the current-voltage (I-V) and capacitance-voltage (C-V) characteristics of these p-n junctions were estimated and analyzed.

Piezoresistive sensitivity, linearity and resistance time drift of polysilicon nanofilms with different deposition temperatures.

Our previous research work indicated that highly boron doped polysilicon nanofilms (≤100 nm in thickness) have higher gauge factor (the maximum is ∼34 for 80 nm-thick films) and better temperature stability than common polysilicon films (≥ 200nm in thickness) at the same doping levels. Therefore, in order to further analyze the influence of deposition temperature on the film structure and piezoresistance performance, the piezoresistive sensitivity, piezoresistive linearity (PRL) and resistance time drift (RTD) of 80 nm-thick highly boron doped polysilicon nanofilms (PSNFs) with different deposition temperatures were studied here. The tunneling piezoresistive model was established to explain the relationship between the measured gauge factors (GFs) and deposition temperature. It was seen that the piezoresistance coefficient (PRC) of composite grain boundaries is higher than that of grains and the magnitude of GF is dependent on the resistivity of grain boundary (GB) barriers and the weight of the resistivity of composite GBs in the film resistivity. In the investigations on PRL and RTD, the interstitial-vacancy (IV) model was established to model GBs as the accumulation of IV pairs. And the recrystallization of metastable IV pairs caused by material deformation or current excitation is considered as the prime reason for piezoresistive nonlinearity (PRNL) and RTD. Finally, the optimal deposition temperature for the improvement of film performance and reliability is about 620 °C and the high temperature annealing is not very effective in improving the piezoresistive performance of PSNFs deposited at lower temperatures.