Impact of chitosan coating of anionic liposomes on clearance rate, mucosal and systemic immune responses following nasal administration in rabbits

Liposomes have been identified as effective immunological adjuvants and have potential for the intranasal and oral delivery of protein antigen. Anionic MLV liposomes were prepared by dehydration–rehydration method. For coating, liposomes were incubated in chitosan solution. Efficiency of coating was confirmed by the evaluation of FITC-labelled chitosan-coated liposomes using a fluorescent microscope. Liposomes morphology and size were studied by optical microscope and size analyzer. Mucoadhesion potential of liposomes was evaluated in human nose by gamma-scintigraphy using ^99mTc-labelled liposomes. Rabbits (4 animals per group) were nasally immunized in weeks 0, 2 and 4 by liposomes encapsulated with 40 Lf TT. Bleedings and lavage collections were taken place in weeks 3 and 6, and IgG and sIgA titers were measured by ELISA method.Liposomes had a mean diameter of 2.38 μm. Loading of TT was 58.7 ± 12.4%. The mucoadhesion (clearance rate from nose) of both coated and non-coated liposomes was similar (P > 0.05). Among the immunized animals, the highest nasal lavage sIgA titers were seen in non-coated liposomes followed by coated ones. The serum IgG titers (2nd bleeding) in animals immunized by both kinds of liposome were similar (P > 0.05), and were lower than the TT solution group (P < 0.05). Immunization by i.m. injection of TT solution resulted in the lowest sIgA and highest IgG titers (P < 0.05) compared with liposomal groups.The results were indicative of good potential of negatively charged liposomes in the induction of mucosal immunity. Coating of liposomes by chitosan, failed to increase both the residence time of liposomes in nasal cavity and systemic responses. Conversely, coated liposomes could not induce the mucosal responses as efficiently as non-coated liposomes. It seems that the coating of liposomes affected their interaction potential with nasal associated lymphoid tissue cells.     

Colloidal stability and drug incorporation aspects of micellar-like PLA–PEG nanoparticles

The drug delivery properties of a series of poly(lactic acid)–poly(ethylene glycol) (PLA–PEG) micellar-like nanoparticles have been assessed in terms of their colloidal stability and their ability to incorporate a water soluble drug. These studies have focused on a range of PLA–PEG copolymers with a fixed PEG block (5 kDa) and a varying PLA segment (3–110 kDa). In aqueous media, these copolymers formed micellar-like assemblies following precipitation from water miscible solvents. There was a controlled increase in the particle size as the molecular weight of the PLA block was increased. The characteristics of the PEG corona were also highly dependent on the PLA moiety. Copolymers with a low molecular weight PLA block (3–15 kDa) formed highly colloidally stable dispersions, with a complete PEG surface coverage. However, increasing the molecular weight of the PLA block resulted in significantly less colloidally stable nanoparticle dispersions, which flocculated in solvents that were significantly better than θ-solvents for the stabilising PEG chains. This can be attributed to a reduced PEG surface coverage and the probable presence of naked PLA ‘patches’ on the particle surface. These larger PLA–PEG nanoparticles (30:5–110:5) were found to be stabilised in the presence of serum components, which are thought to adsorb into the gaps on the particle surface and prevent flocculation. All of the dispersions were found to be stable under physiological conditions and therefore suitable for in vivo administration. A reasonable loading (3.1% w/w) of the micellar-like PLA–PEG 30:5 nanoparticles with the water soluble drug procaine hydrochloride was achieved. The incorporated drug was found to have no effect on the nanoparticle structure or recovery, which can be attributed to the micellar character of these assemblies and the presence of the stabilising PEG chains.     

Residue depletion of valnemulin in swine tissues after oral administration

The depletion profile of valnemulin (VLM) was studied in healthy piglets after oral administration of a premix. Thirty pigs were given doses of 7.5 mg/kg body weight/day in the feed for 21 days. One control and five medicated piglets were randomly selected for sacrifice at 0.25, 0.5, 1, 2 and 3 days post-treatment. The residue concentrations of VLM in swine muscle, liver and kidney were detected using high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). The highest residue concentrations of VLM were attained in 0.25 day, and all of the samples were below the maximum residue limit (MRL) recommended by the European Medical Evaluation Agency (EMEA) at 0.5 day post-treatment. The residue concentrations of swine liver were significantly higher than those of kidney and muscle, which indicated liver to be the target tissue for VLM. The withdrawal period of VLM with oral administration was 24 hours.     

The intragastrointestinal fate of paclitaxel-loaded micelles: Implications on oral drug delivery

The goal of the present study is to elucidate the intragastrointestinal fate of micellar delivery systems by monitoring fluorescently labeled different micelles and the model drug paclitaxel (PTX). Both in vitro and ex vivo leakage studies showed fast PTX release in fluids while micelles remained intact, except in fed-state simulated intestinal fluid and fasted-state pig intestinal fluid, thus referring to the intact absorption of micelles and PTX leakage in the gastrointestinal tract with d-α-tocopherol polyethylene glycol 1000 succinate (TPGS) micelles showing higher stability than other micelles. All groups of micelles were absorbed intact in Caco-2 and Caco-2/HT29-MTX cell models and the absorption of TPGS micelles was found to be higher than other micelles. The transport of the micelles across Caco-2/Raji (1.6%–3.5%), Caco-2 (0.8%–1%), and Caco-2/HT29-MTX (0.58%–1%) cell monolayers further verified the absorption of micelles and their subsequent transport; however, more TPGS micelles transported across cell monolayers than other groups. Moreover, the histological examination also confirmed that micelles entered the enterocytes and were transported to basolateral tissues and TPGS showed the stronger ability of penetration than other groups. Thus, these results are succinctly presenting the absorption of intact micelles in GIT confirmed by imaging evidence with prior leakage of the drug, uptake by enterocytes and the transport of micelles that survive the digestion by enterocytes and mainly by microfold cells in material nature dependent way with TPGS showing better results than other groups. In conclusion, these results identify the mechanism by which the gastrointestinal tract processes micelles and point to the likely use of this approach in the design of micelles-based therapies.     

Incorporation of methamphetamine and amphetamine in human hair following controlled oral methamphetamine administration

Background

Although hair testing is well established for the assessment of past drug exposure, uncertainties persist about mechanisms of drug incorporation into hair and interpretation of results. The aim of this study was to administer methamphetamine (MAMP) under controlled conditions as a model drug to investigate drug incorporation into human hair.

Material and methods

Seven volunteers with a history of stimulant use received 4 × 10 mg (low) doses of sustained release S-(+)-MAMP HCl within 1 week, with weekly head hair samples collected by shaving. 3 weeks later, 4 of them received 4 × 20 mg (high) doses. After extensive isopropanol/phosphate buffer washing of the hair, MAMP and its metabolite amphetamine (AMP) concentrations were determined in all weekly hair samples by LC–MS–MS in selected reaction monitoring mode with the undeca- and deca-deuterated drugs, respectively, as internal standards (LLOQ, 0.005 ng mg⁻¹).

Results

MAMP T_max occurred from 1 to 2 weeks after both doses, with C_max ranging from 0.6 to 3.5 ng mg⁻¹ after the low and 1.2 to 5.3 ng mg⁻¹ after the high MAMP doses. AMP C_max in hair was 0.1–0.3 ng mg⁻¹ and 0.2–0.5 ng mg⁻¹, respectively, for low and high doses. Highly dose-related concentrations within subjects, but large variability between subjects were observed. MAMP concentrations were above the 0.2 ng mg⁻¹ cut-off for at least 2 weeks following administration of both low and high doses. The overall AMP/MAMP ratio ranged from 0.07 to 0.37 with a mean value of 0.15 ± 0.07, and a median of 0.13. The percentage of MAMP and AMP removed with the washing procedure decreased with time after administration. A strong correlation was found between area under the curve of MAMP (r² = 0.90, p = 0.00) and AMP (r² = 0.94, p = 0.00) concentrations calculated for the 3-week period following administration and the total melanin concentration in hair. Significant correlations were observed also between C_max and melanin.

Conclusions

This study demonstrated that despite large inter-individual differences, the incorporation of MAMP and AMP into hair is dose-related with much of the observed scatter of MAMP and AMP concentrations explained by melanin concentration in hair.     

LC‐ESI‐MS/MS analysis of quercetin in rat plasma after oral administration of biodegradable nanoparticles

A simple, rapid and sensitive LC‐MS/MS method was developed and validated for the determination of free quercetin in rat plasma, using fisetin as internal standard. The detection was performed by negative ion electrospray ionization under selected reaction monitoring. Chromatographic separation (isocratic elution) was carried out using acetonitrile–10 m m ammonium formate (80:20, v/v) with 0.1% v/v formic acid. The lower limit of quantification (4.928 ng/mL) provided high sensitivity for the detection of quercetin in rat plasma. The linearity range was from 5 to 2000 ng/mL. Intra‐ and inter‐day variability (RSD) of quercetin extraction from rat plasma was <4.19 and 1.37% with accuracies of 98.77 and 99.67%. The method developed was successfully applied for estimating free quercetin in rat plasma, after oral administration of quercetin‐loaded biodegradable nanoparticles (QLN) and quercetin suspension. QLN (C_max, 1277.34 ± 216.67 ng/mL; AUC, 17,458.25 ± 3152.95 ng hr/mL) showed a 5.38‐fold increase in relative bioavailability as compared with quercetin suspension (C_max, 369.2 ± 108.07 ng/mL; AUC, 3276.92 ± 396.67 ng hr/mL). Copyright © 2015 John Wiley & Sons, Ltd.     

Determination of midazolam in rabbit plasma by GC and LC following nasal and ocular administration

GC with nitrogen phosphorus detection and HPLC with UV detection were used to determine midazolam (MDZ) levels in rabbit plasma following ocular and nasal administration. For GC with nitrogen phosphorus detection, the analyte was extracted from the plasma using a three‐step liquid–liquid extraction including extraction with an isopropanol/butyl chloride mixture in an alkaline solution, followed by extractions with 1 M HCl, and finally with an alkaline solution of butyl chloride. The recovery of MDZ was dependent on the sample alkalization time prior to the final extraction. The procedure increased the recovery of MDZ up to 99.6%. Improved sample preparation led to a significant increase in the sensitivity of the determination by GC with nitrogen phosphorus detection. The achieved detection limit was 0.34 ng/mL, which is ten times lower than that obtained using HPLC with UV detection. The small plasma volume was another advantage of the GC with nitrogen phosphorus detection method (200 μL per assay). Both administration routes of the anesthetic (nasal and ocular) resulted in comparable plasma MDZ levels. Kinetic simulation of the MDZ plasma was performed for both administration routes.     

Investigating the generation of ferrous sulfide nanoparticles in the produced fluid after acidizing oil wells and its influence on emulsifying stability between oil and water

Studies show that after acidizing operation of oil wells using the alkali/surfactant/polymer (ASP) flooding technology, the produced fluid is emulsified. Since the produced emulsion is stable, it affects the oil–water separation performance. In order to analyze the generation of stable emulsion in the produced fluid after acidizing an oil well, innovative separation experiments were carried out on real oil wells. During the experiments, solid particles in the middle layer of the emulsifying system in the produced fluid after acidizing ASP flooding were extracted and characterized. The generation of the stable emulsifying system in the produced fluid was studied through stability experiments and molecular dynamics simulations. The results showed that the synergistic effect of ferrous sulfide nanoparticles and surfactants was the fundamental reason for the strong emulsifying stability of the produced liquid after acidizing of the ternary composite system. The generation of ferrous sulfide solid particles mainly included two steps. First, sulfate reducing bacteria in injected water by ASP flooding reacted with sulfate in formation water to form hydrogen sulfide. Then, the hydrogen sulfide reacted with iron metal in oil wells and casing of wellbore to form ferrous sulfide particles. It was found that surfactants are adsorbed on the surface of ferrous sulfide nanoparticles. Subsequently, the control ability of surfactant on oil and water phases in the liquid film was enhanced. The performed analyses demonstrate that the adsorption of solid particles to the oil phase was enhanced, while the free motion of molecules in the oil phase at the liquid film position was weakened. The strength of the interfacial film between oil and water was further increased by the synergistic effect of ferrous sulfide nanoparticles and surfactant. The present study is expected to provide a guideline for a better understanding of the efficient treatment of produced fluids in ASP flooding.     

The formation of hydrophobic inorganic nanoparticles in the presence of amphiphilic copolymers

The presented paper describes a novel procedure for the preparation of inorganic nanoparticles and their surface functionalization in situ dedicated to an application in technical polymers. Using an inverse emulsion technique and amphiphilic block or statistical copolymers as stabilizers, a broad variety of nanoparticles such as ZnO, CdS, MgCO₃, Ni, or Cu can be prepared. The amphiphilic polymers serve not only as surface active compounds in the emulsion but also to hydrophobize the inorganic particles as they remain adsorbed on the surface after the precipitation. As a consequence of the high degree of surface coverage by polymer chains, organic solvents are able to redisperse these particles in the aggregate free manner. The utilization of the block copolymers instead of statistical copolymers resulted in the formation of the particles, which were larger in size and possessed a much broader size distribution. The chemical nature of the adsorbed polymer layer on the particle surface is crucial to the preparation of polymer nanocomposites. The primary goal of this contribution is to demonstrate the universality of such a one-pot synthetic procedure, which was found to be relevant for industrial use.     

The role of pore size and structure on the thermal stability of gold nanoparticles within mesoporous silica

Highly dispersed gold particles (<2 nm) were synthesized within the pores of mesoporous silica with pore sizes ranging from 2.2 to 6.5 nm and different pore structures (2D-hexagonal, 3D-hexagonal, and cubic). The catalysts were reduced in flowing H2 at 200 degrees C and then used for CO oxidation at temperatures ranging from 25 to 400 degrees C. The objective of this study was to investigate the role of pore size and structure in controlling the thermal sintering of Au nanoparticles. Our study shows that sintering of Au particles is dependent on pore size, pore wall thickness (strength of pores), and pore connectivity. A combination of high-resolution TEM/STEM and SEM was used to measure the particle size distribution and to determine whether the Au particles were located within the pores or had migrated to the external silica surface.     

Multiclass analysis of illicit drugs in plasma and oral fluids by LC-MS/MS

An analytical procedure for the simultaneous determination in human plasma and oral fluids of several illicit drugs belonging to different chemical and toxicological classes is presented. Amphetamine, methamphetamine, morphine, 6-monoacetylmorphine, methylenedioxyamphetamine, methylenedioxyethylamphetamine, methylenedioxymethamphetamine, cocaine, benzoylecgonine, tetrahydrocannabinol, carboxytetrahydrocannabinol, ketamine, and phencyclidine have been quantified in real samples using a very rapid sample treatment, basically a protein precipitation. The quantitative analysis was performed by liquid chromatography–tandem mass spectrometry and has been fully validated. All the analytes were detected in positive ionization mode using a TurboIonSpray source, except carboxytetrahydrocannabinol, which was detected in negative ionization mode. The use of a diverter valve between the column and the mass spectrometer allows the preservation of the ion source performances for high-throughput analysis. Figure Diverter system     

Synthesis of novel poly(ethylene glycol) supported benzazepines: the crucial role of PEG on the selectivity of an intramolecular Heck reaction

Poly(ethylene glycol) (PEG 3400) was used as a soluble polymeric support for the synthesis of a series of novel benzazepines. The key step for the preparation of these heterocycles was a phosphine-free palladium-catalyzed Heck reaction. Palladium nanoparticles formed during the course of the reaction were characterized. The presence of PEG 3400 influenced the outcome of the reaction in terms of selectivity.     

The influence of micro- and nanoparticles on model atomically flat surfaces on crystallization of polyethylene

Crystallization of high density polyethylene (PE) from the melt on model atomically flat solid surfaces decorated with micro- and nanoparticles of gold or NaCl of different size and densities is investigated. The morphology of the contact layer of PE after its detachment from the support is studied using atomic force microscopy (AFM). It is shown that the nucleating and ordering effect of the solid on PE crystallization depends to a large extend on the nanostructure of its surface, in particular on the size of the atomically flat domains and on the presence of nanoscopic obstacles. The minimum size of the flat domain which can significantly influence the PE crystallization is estimated to be of the order of 150 nm.     

Monitoring of the stability of cocaine and some metabolites in water and oral fluid by a newly developed CE method

A new CE method was here developed, in order to study the stability of cocaine and some of its metabolites in water and in oral fluid. At first, standard mixtures of cocaine (COC), benzoylecgonine (BE) and cocaethylene (COET) in water were used to study the optimal CE parameters to separate the three compounds. Voltage, sample temperature and pH were investigated, and 25 kV, 25°C and a pH of 4.7 were selected to achieve the best separation. The stability of the three compounds in water and oral fluid was then monitored by applying the previously developed method. Three different storage temperatures (8, 25 and 37°C) were selected and analyses during a week were performed. A decrease of COC and COET peak areas and an increase of BE peak area were observed over time at 25 and 37°C. In addition, in oral fluid, the presence of enzymes and other proteins, and the differences in the molecular structures between COC and COET, caused a stronger degradation of the first compound. Instead, when samples were stored at a low temperature (8°C), the peak areas of the compounds did not vary. Thus, the use of this storage temperature is recommended, above all when sample must be analyzed after a relatively long time.     

Different acute effects of oral and intratracheal administration of disodium arsenate and gallium arsenide on heme synthesis in rats

The acute influences of arsenic compounds on the metabolism of porphyrins and heme in various organs of rats after oral or intratracheal administration of disodium arsenate (Na₂HAsO₄) and gallium arsenide (GaAs) were examined and compared. For the oral administration experiments, 21 or 84 mg of Na₂HAsO₄, or 2 or 4 g of GaAs, per cm³ saline per kg body weight of each animal was administered to Jcl: Wistar male rats and the organs were removed after exsanguination from the vein of the right axilla under anesthesia with ether, 16 h after administration. In the case of intratracheal administration, rats given 8.2 or 16.4 mg of Na₂HAsO₄, or 0.2 or 0.4 g GaAs per cm³ saline per kg body weight were examined under the same experimental conditions as for the administration route. Increase in the body weight of rats was suppressed after intratracheal administration of the two arsenic compounds. In these rats the hematocrit value increased significantly. These changes were not shown by the orally administered rats. Elevation in δ-aminolevulinate synthase (ALA-S, EC 2.3.1.37) activity in erythroblasts by Na₂HAsO₄ was much higher after intratracheal administration than after oral administration. Suppression in the activities of δ-aminolevulinate dehydratase (ALA-D, EC 4.2.1.24) and porphobilinogen deaminase (PBG-D, EC 4.3.1.8) in peripheral erythrocytes by Na₂HAsO₄ and GaAs were stronger by intratracheal administration than by the oral route. Influences of GaAs on the activity of PBG-D in rat liver were shown to be more effective by oral administration than by the intratracheal route. Oral administration of Na₂HAsO₄ and GaAs had a stronger suppression effect on the activities of ALA-D and PBG-D in rat kidney. It seems from these results that the different extents of the influence of arsenic compounds might depend on the routes of intake.     

Synthesis and characterization of silica-supported Pd nanoparticles and its application in the Heck reaction

Well-dispersed palladium nanoparticles immobilized onto modified silica(SiO 2-pr-NH-cyanuric-SH) have been prepared in some facile steps.The catalyst exhibits high catalytic activity in the Heck reaction,and can be easily recovered and reused without significant loss of its activity in several runs.     

ZnO nanoparticles as chain elasticity reducer and structural elasticity enhancer: Correlating the degradating role and localization of ZnO with the morphological and mechanical properties of PLA/PP/ZnO nanocomposite

The main purpose of this study was to investigate the effect of zinc oxide (ZnO) nanoparticles on the morphological, mechanical, thermal, and rheological properties of PLA/PP blend. In this regard, nanocomposites containing 1, 3, and 5 wt% of ZnO nanoparticles were prepared by melt mixing. In addition, three different mixing procedures were adopted to study their effects on the microstructure of nanocomposites. The rheological behaviors demonstrated a higher elasticity and less compatibility for two phases in the case of nanocomposites containing nanoparticles in harmony with the morphological observations. Accordingly, it was correlated to the elasticity originating from the interphase, anticipated coalescence of dispersed particles as a result of degradation of PLA chains triggered by ZnO nanoparticles (ZnO‐NPs) and also agglomeration of ZnO‐NPs depending on the content of nanoparticles and chosen mixing procedure. It was also found that mixing method puts a remarkable influence on the microstructure and rheological behavior of nanocomposites. Results of mechanical characterizations and thermogravimetric analysis (TGA) also confirmed the degradation induced by ZnO nanoparticles.     

The effect of silica nanoparticles on the stability of aqueous foams

An experimental study was performed on aqueous foams stabilized by a mixture of hexadecyltrimethylammonium bromide (HTAB) and negatively-charged silica nanoparticles. The effects of the nanoparticles on the stability of foams at different HTAB concentrations were investigated. The foams were characterized by measuring their foamability and stability. Rheological behavior of the foams was also studied. Furthermore, rheology of the air–water interfaces was studied in the linear and nonlinear deformation ranges. The thickness of the monolayer at the interface was measured. The actual size of the silica nanoparticles at the air–water interface was measured by transmission electron microscopy. Based on these measurements, the interaction between the monolayers across the foam film containing HTAB and nanoparticles was investigated. Smaller silica nanoparticles (i.e. diameter less than 10?nm) adsorbed at the air–water interface whereas the larger particles remained in the sub-phase or in the bulk liquid phase. It was found that these nanoparticles strongly influenced the foaming behavior at the low HTAB concentrations (i.e. below the CMC). A Langmuir-type monolayer was formed. The presence of the nanoparticles at the air–water interface provided mechanical strength to the foam films and prevented their rupture. This hindered coalescence of the bubbles, which resulted in a stable foam.     

Synthesis of nickel nanoparticles supported on metal oxides using electroless plating: Controlling the dispersion and size of nickel nanoparticles

Nickel nanoparticles supported on metal oxides were prepared by a modified electroless nickel-plating method. The process and mechanism of electroless plating were studied by changing the active metal (Ag) loading, acidity, and surface area of metal oxides and were characterized by UV–vis spectroscopy, transmission electron microscopy, scanning electron microscopy, and H₂ chemisorption. The results showed that the dispersion of nickel nanoparticles was dependent on the interface reaction between the metal oxide and the plating solution or the active metal and the plating solution. The Ag loading and acidity of the metal oxide mainly affected the interface reaction to change the dispersion of nickel nanoparticles. The use of ultrasonic waves and microwaves and the change of solvents from water to ethylene glycol in the electroless plating could affect the dispersion and size of nickel nanoparticles.     

The relevance of boranes and metallaboranes to the structures of p-block element nanoparticles

Recent d-block element metallaborane chemistry, in which metal identity is varied with constant ancillary ligand, demonstrates how the rising energy of the d orbitals as one moves to earlier metals gives rise to non spherical cluster shapes that permit low formal cluster electron counts. In essence, the separation of frontier orbitals from “nonbonding” orbitals required by the isolobal analogy breaks down and the resulting mixing generates additional high-lying empty orbitals concurrently with shape change. A very similar mechanism explains recent p-block cluster chemistry albeit with variation in extent of external cluster ligation as the variable and separation of external lone pair orbitals from cluster bonding as the problem. Sensible, novel explanations of the shape/electron count relationships can be discovered for large group 13 clusters by recognizing the perturbation in cluster orbital energies when stabilization by ligand interactions is removed. These observations are pertinent to an understanding of large p-block clusters with internal atoms often referred to as nanoparticles.