Aqueous re-dispersibility characterization of spray-dried hollow spherical silica nano-aggregates

Hollow spherical aggregates of biocompatible silica nanoparticles are produced by the spray drying technique to facilitate the delivery of the nanoparticles to the lung for potential drug delivery applications. The large geometric size (d_G > 5 µm) and the low density (ρ_eff ≈ 0.3 g/cm³) of the nano-aggregates are specifically formulated to achieve high aerosolization efficiency and an effective lung deposition. The nano-aggregates must readily re-disperse into the primary nanoparticles in an aqueous medium for the nanoparticles to perform their intended therapeutic functions. An aqueous re-dispersibility characterization technique based on the turbidity level measurement is developed for this purpose. A water-soluble excipient (i.e. mannitol), which forms “excipient bridges” interconnecting the nanoparticles, is included in the spray-drying formulation to produce readily re-dispersible nano-aggregates. The nano-aggregate aqueous re-dispersibility depends on (1) the silica: mannitol concentration ratio and (2) the degree of hollowness, where nano-aggregates with a higher shell thickness to particle radius ratio exhibit weaker re-dispersibility due to the poor particle wetting. The spray-drying condition and the silica: mannitol ratio, which lead to the production of highly re-dispersible nano-aggregates having the desired morphology, are determined. The promising results signify the potential application of hollow spherical silica nano-aggregates as an inhaled drug delivery vehicle.     

Optimizing aerosolization efficiency of dry-powder aggregates of thermally-sensitive polymeric nanoparticles produced by spray-freeze-drying

Dry powder inhaler (DPI) delivery of therapeutic nanoparticles requires the nanoparticles to be transformed into inhalable micro-scale aggregate structures (i.e. nano-aggregates). The present work details the spray-freeze-drying (SFD) production of dry-powder aggregates of thermally-sensitive polymeric nanoparticles. Specifically, the aim is to optimize the aerosolization efficiency of the nano-aggregates, while keeping the morphology, production yield, flowability, and aqueous reconstitution in the desirable range. For this purpose, the effects of SFD process parameters (i.e. atomization rate, feed concentration, and feed rate) and freeze-drying adjuvant formulation on the nano-aggregate characteristics are examined. Low melting-point poly (caprolactone) (PCL) nanoparticles are used as the model nanoparticles. Mannitol and leucine are used as the hydrophilic and hydrophobic adjuvants, respectively. Large spherical porous nano-aggregates, where PCL nanoparticles are physically dispersed in the porous adjuvant matrix, have been produced. The presence of mannitol is crucial in ensuring that the nano-aggregates readily reconstitute into individual nanoparticles upon exposure to an aqueous environment, so that they can perform their intended therapeutic functions. The presence of leucine, on the other hand, is mandatory to obtain high aerosolization efficiency as its presence reduces the nano-aggregate tendency to agglomerate. At the optimal condition, nano-aggregates exhibiting ED (Emitted Dose) ≈ 95%, FPF (Fine Particle Fraction) ≈ 30%, and MMAD (Mass Median Aerodynamic Diameter) ≈ 5.3 μm, which are comparable to the values obtained in commercial DPI, have been produced. The results signify the potential of SFD to be employed in the production of inhalable dosage form of thermally-sensitive therapeutic nanoparticles.     

Spray drying formulation of hollow spherical aggregates of silica nanoparticles by experimental design

The present work employs an experimental design methodology to optimize the spray-drying production of micron-size hollow aggregates of biocompatible silica nanoparticles that are aimed to serve as drug delivery vehicles in inhaled photodynamic therapy. To effectively deliver the nanoparticles to the lung, the aerodynamic size (d_A) of the nano-aggregates, which is a function of the geometric size (d_G) and the degree of hollowness, must fall within a narrow range between 2 and 4 μm. The results indicate that (1) the feed concentration, (2) the feed pH, and (3) the ratio of the gas atomizing flow rate to the feed rate are the three most significant parameters governing the nano-aggregate morphology. Spray drying at a low pH (<7) and at a low feed concentration (<1%, w/w) generally results in nano-aggregates having small geometric and aerodynamic sizes (d_A = d_G ≈ 3 μm) with a relatively monodisperse size distribution. Spray drying at a higher feed concentration produces nano-aggregates having a larger d_G but with a multimodal particle size distribution. A trade-off therefore exists between having large d_G to improve the aerosolization efficiency and obtaining a uniform particle size distribution to improve the dose uniformity.     

Self-dissociation of water-soluble PANa/ETC nano-aggregates

Complexation between poly(sodium acrylate) (PANa) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide methiodide (ETC) in water, which leads to the formation of vesicle-like aggregates, was studied. Different from reported nano-aggregates of polymer complexes that may dissociate when being stimulated, the nano-aggregates of PANa/ETC complexes dissociate automatically in the aqueous solution at ambient environment, exhibiting a behavior similar to that of the nano-aggregates composed of degradable polymers. In the newly formed nano-aggregates, there are hydrophobic domains with a hydrophobicity close to that of hexane. Along with the dissociation, the hydrophobic domains vanish gradually.     

双亲纳米颗粒在选择性溶剂中的自组装行为：耗散粒子动力学模拟

接枝聚合物纳米颗粒在构筑多级功能性纳米材料方面具有很大潜力,但其在选择性溶剂中自组装相图却鲜见报道。利用耗散粒子动力学模拟研究了溶剂选择性、接枝聚合物链长度以及亲水、疏水聚合物链比例等因素对双亲纳米颗粒自组装行为的影响,并绘制了自组装形态相图。结果显示,随着浓度的增大,双亲纳米颗粒逐渐自组装成球状、棒状、二维膜、纳米膜孔等丰富纳米结构。不仅如此,溶剂与亲水、疏水聚合物相容性差异较小时（a_S-HL=40k_BT/R_c,a_S-HB=50k_BT/R_c）,双亲纳米颗粒自组装形成层状纳米结构,在较高浓度时,形成规则的多孔网络结构。研究发现,双亲纳米颗粒浓度和接枝聚合物的链长以及亲水、疏水聚合物链比例是调控双亲纳米颗粒自组装形态的关键因素。鉴于双亲纳米颗粒丰富的自组装行为,它在气体分离、检测、载药、催化剂载体等领域有着很大的潜在应用价值。     

Suspensions of Iron Oxide Nanoparticles Stabilized by Anionic Surfactants

Two common anionic surfactants, sodium oleate (SO) and sodium dodecyl benzene sulfonate (SDBS) were used to re‐suspend iron oxide nanoparticles in aqueous solutions. At certain SO concentrations, the SO formulations produced highly stable suspensions. In contrast, SDBS‐stabilized nanoparticles exhibited poor stability at all concentrations. The adsorption isotherm of SO on iron oxide nanoparticles revealed that stable suspensions were obtained when the equilibrium SO concentration (after adsorption) reached its critical micelle concentration (CMC). At this “optimal” condition, the maximum SO adsorption was reached, and the zeta‐potential of the particles was highly negative (～ ?50 mV). According to the SO isotherm, this optimal formulation coincided with the formation of a highly compact SO bilayer. The SDBS isotherm, on the other hand, revealed that SDBS is not strongly adsorbed on the surface of iron oxide nanoparticles and that is likely that a patchy, loosely packed bilayer, is formed on the surface of the iron oxide nanoparticles when the equilibrium SDBS concentration reaches its CMC. The DLVO theory confirmed the connection between formulation conditions and the corresponding stability. This works confirmed that the formation of a surfactant bilayer is an important element in producing stable nanoparticle suspensions with anionic surfactants. It was also confirmed that for anionic surfactants, electrostatic repulsions are an important factor in establishing an energy barrier against flocculation. This work also introduced two more elements into the design of nanoparticle suspensions. The first element is that, in order to ensure the best possible dispersion, the surfactant concentration in solution at equilibrium with the adsorbed surfactant should be close or slightly above its CMC. The second element is that the molecular structure of the surfactant should facilitate the formation of closely packed bilayers.     

Aggregated Nanoparticle Morphology Effects on Membrane Filtration

Nanoparticles are considered potential environmental contaminants because of reported toxicity to biota in the environment. As such, there is interest in understanding how to remove nanoparticles from waters. This study investigated membrane filtration behaviors of 70-nm alumina oxide nanoparticle when aggregated under diffusion limited aggregation and reaction limited aggregation regimes. In this study, nanoparticles were aggregated under conditions of high and low ionic strength to form aggregates of different morphology. Aggregates were filtered using a hydrophilic polyvinylidene fluoride membrane with a pore size of 0.22 µm, 100% nanoparticle removal efficiencies were obtained regardless of aggregation conditions used. Aggregate morphology was quantified by measured fractal dimensions. Fractal structure differences coincided with measured filtration resistance values. Low porosity aggregates provided a filtration resistance 43% greater than high porosity aggregates of the same effective size. Model predictions for measured specific resistance values were improved through incorporation of compressibility indexes. In order to obtain a porous structure with less resistance, a fast coagulation process is suggested for nanoparticle removal.     

High‐Throughput Miniaturized Screening of Nanoparticle Formation via Inkjet Printing

The self‐assembly of specific polymers into well‐defined nanoparticles (NPs) is of great interest to the pharmaceutical industry as the resultant materials can act as drug delivery vehicles. In this work, a high‐throughput method to screen the ability of polymers to self‐assemble into NPs using a picoliter inkjet printer is presented. By dispensing polymer solutions in dimethyl sulfoxide (DMSO) from the printer into the wells of a 96‐well plate, containing water as an antisolvent, 50 suspensions are screened for nanoparticle formation rapidly using only nanoliters to microliters. A variety of polymer classes are used and in situ characterization of the submicroliter nanosuspensions shows that the particle size distributions match those of nanoparticles made from bulk suspensions. Dispensing organic polymer solutions into well plates via the printer is thus shown to be a reproducible and fast method for screening nanoparticle formation which uses two to three orders of magnitude less material than conventional techniques. Finally, a pilot study for a high‐throughput pipeline of nanoparticle production, physical property characterization, and cytocompatibility demonstrates the feasibility of the printing approach for screening of nanodrug delivery formulations. Nanoparticles are produced in the well plates, characterized for size and evaluated for effects on metabolic activity of lung cancer cells.     

Nanoparticle formulation of poly(?-caprolactone-co-lactide)-d-α-tocopheryl polyethylene glycol 1000 succinate random copolymer for cervical cancer treatment

Cervical cancer remains a critical problem that is second only to breast cancer affecting women worldwide. The objective of this study was to develop formulation of docetaxel-loaded biodegradable poly(?-caprolactone-co-lactide)-d-α-tocopheryl polyethylene glycol 1000 succinate (PCL-PLA-TPGS) nanoparticles for cervical cancer chemotherapy. A novel random copolymer, PCL-PLA-TPGS, was synthesized from ?-caprolactone, lactide and d-a-tocopheryl polyethylene glycol 1000 succinate (TPGS) by ring-opening polymerization. The obtained polymers were characterized by ¹H NMR, FTIR, GPC and TGA. The docetaxel-loaded PCL-PLA-TPGS nanoparticles were prepared by a modified solvent extraction/evaporation technique and characterized in terms of size and size distribution, morphology, surface charge and physical state of encapsulated docetaxel. Cellular uptake and in vitro cytotoxicity of nanoparticle formulations were done in comparison with commercial formulation Taxotere^® to investigate the efficacy of PCL-PLA-TPGS nanoparticles. In vitro cellular uptakes of such nanoparticles were investigated with CLSM, demonstrating the coumarin 6-loaded PCL-PLA-TPGS nanoparticles could be internalized by Hela cells. In vitro cancer cell viability experiment showed that judged by IC₅₀, the PCL-PLA-TPGS nanoparticle formulation was found to be more effective in cell number reduction than the Taxotere^® after 48 h (p < 0.05), 72 h (p < 0.05) treatment. In conclusion, the PCL-PLA-TPGS copolymer could be acted as a novel and promising biologically active polymeric matrix material for nanoparticle formulation in cervical cancer treatment.     

Inhaled nanomaterials and the respiratory microbiome: clinical,immunological and toxicological perspectives

Our development and usage of engineered nanomaterials has grown exponentially despite concerns about their unfavourable cardiorespiratory consequence, one that parallels ambient ultrafine particle exposure from vehicle emissions. Most research in the field has so far focused on airway inflammation in response to nanoparticle inhalation, however, little is known about nanoparticle-microbiome interaction in the human airway and the environment. Emerging evidence illustrates that the airway, even in its healthy state, is not sterile. The resident human airway microbiome is further altered in chronic inflammatory respiratory disease however little is known about the impact of nanoparticle inhalation on this airway microbiome. The composition of the airway microbiome, which is involved in the development and progression of respiratory disease is dynamic, adding further complexity to understanding microbiota-host interaction in the lung, particularly in the context of nanoparticle exposure. This article reviews the size-dependent properties of nanomaterials, their body deposition after inhalation and factors that influence their fate. We evaluate what is currently known about nanoparticle-microbiome interactions in the human airway and summarise the known clinical, immunological and toxicological consequences of this relationship. While associations between inhaled ambient ultrafine particles and host immune-inflammatory response are known, the airway and environmental microbiomes likely act as intermediaries and facilitate individual susceptibility to inhaled nanoparticles and toxicants. Characterising the precise interaction between the environment and airway microbiomes, inhaled nanoparticles and the host immune system is therefore critical and will provide insight into mechanisms promoting nanoparticle induced airway damage.     

Dual Agent Loaded PLGA Nanoparticles Enhanced Antitumor Activity in a Multidrug-Resistant Breast Tumor Eenograft Model

Multidrug-resistant breast cancers have limited and ineffective clinical treatment options. This study aimed to develop PLGA nanoparticles containing a synergistic combination of vincristine and verapamil to achieve less toxicity and enhanced efficacy on multidrug-resistant breast cancers. The 1:250 molar ratio of VCR/VRP showed strong synergism with the reversal index of approximately 130 in the multidrug-resistant MCF-7/ADR cells compared to drug-sensitive MCF-7 cells. The lyophilized nanoparticles could get dispersed quickly with the similar size distribution, zeta potential and encapsulation efficiency to the pre-lyophilized nanoparticles suspension, and maintain the synergistic in vitro release ratio of drugs. The co-encapsulated nanoparticle formulation had lower toxicity than free vincristine/verapamil combinations according to the acute-toxicity test. Furthermore, the most effective tumor growth inhibition in the MCF-7/ADR human breast tumor xenograft was observed in the co-delivery nanoparticle formulation group in comparison with saline control, free vincristine, free vincristine/verapamil combinations and single-drug nanoparticle combinations. All the data demonstrated that PLGANPs simultaneously loaded with chemotherapeutic drug and chemosensitizer might be one of the most potential formulations in the treatment of multidrug-resistant breast cancer in clinic.     

The fabrication and characterization of inkjet-printed polyaniline nanoparticle films

This paper reports on the fabrication and characterization of electrodes modified with conducting polymer nanoparticle films, produced via inkjet printing. The polyaniline nanoparticle formulations were deposited via a desktop inkjet printer onto screen-printed carbon-paste electrodes (SPE), polyethylene terephthalate (PET) and gold-PET and their morphology studied at a range of length scales using profilometry, scanning electron microscopy and atomic force microscopy. The deposited films were found to form continuous polymer films depending upon film thickness, which was in turn dependent on the number of prints performed. The inkjet-printed films exhibited a smooth morphology on the SPEs at the micro-dimensional scale, as a result of the aggradation and coalescing of the nanoparticles upon deposition. The resulting modified electrodes were both conductive and electroactive, possessing good reversible polyaniline electrochemistry. Such a combination of materials and processing offers the potential of producing a range of low cost, solid state devices such as sensors, actuators and electrochromic devices.     

农药残留及其纳米颗粒的毒性问题

简述了农药施用后在环境中的残留及相应的毒性问题。在常用农药剂型中,有些农药的颗粒非常细小,甚至达到纳米水平,而纳米颗粒则具有独特的理化性质,但农药颗粒的纳米效应对植物病虫草害的作用未引起足够的重视,这方面的研究尚属空白。现今,随着加工技术的发展,新的农药剂型不断问世,商业化“纳米农药”即将进入市场,然而,纳米农药能否大幅度提高药效以及是否真正绿色环保尚需严格的试验验证;相反,纳米农药由于其超细颗粒可能具有的纳米毒性继而引发新的环境污染问题却令人担忧。     

Sonochemical Preparation and Properties of Pt–3Y-TZP Nano-Composites

A uniformly aggregated 3 mol% yttria-stabilized tetragonal zirconia nano-powder (3Y-TZP) was prepared using thermal hydrolysis and the ultrasonic deagglomeration technique. The possibility of nano-engineering of Pt–3Y-TZP composite aggregates was studied. The as-synthesized Pt nano-particles (∼2 nm) were impregnated into zirconia nano-aggregates (20–45 nm). The morphology manipulation technique allowed production of the composite zirconia-based aggregates in which a significant fraction of the Pt particles was embedded into the densified zirconia aggregates. Using the colloidal technique and low-temperature (1150°C) sintering, we prepared the Pt-zirconia (0.5–1.5 wt% of platinum) nano-composites with average 3Y-TZP grain sizes of 120 nm, and with the platinum grains size in the range of 20–60 nm. The catalytic properties of composite Pt–3Y-TZP nano-composites were studied and described.     

Characterization of surface modified carbon nanoparticles by low temperature plasma treatment

The carbon nanoparticles derived from polypyrrole were treated with oxygen and ammonia radio-frequency plasma. Micro-attenuated total reflection Fourier transform infrared, element analysis, and X-ray photoelectron spectroscopy analyses were performed to confirm the incorporation of polar functional groups onto the carbon nanoparticles. Moreover, the morphology of plasma treated carbon nanoparticles was retained without nanoparticle aggregation. The plasma treated carbon nanoparticles exhibited the enhanced dispersibility in aqueous solution, compared to the pristine carbon nanoparticles.     

Controlled mesoporous film formation from the deposition of electrosprayed nanoparticles

Thin films of controlled morphology were fabricated by electrospray drying a colloidal nanoparticle suspension using a conductive and volatile solvent and impacting the nanoparticles on a substrate. Three parameters were used for control: impact velocity, size of the nanoparticles or nanoparticle agglomerates, and solvent volatility. The impact velocity was controlled by charging nanoparticles through electrospray dispersion and varying the electric field driving the particle impaction. It was found that the structure is governed by the relative importance of charged particle drift imposed by the external electric field and the thermal velocity due to Brownian motion. Peclet number correlates with the morphology of the deposit where columnar structures result from high Pe, corresponding to ballistic deposition and porous, fractal-like structures result from small Pe. These patterns match predictions based on Monte Carlo simulations in the literature. For dispersions with higher nanoparticle concentrations, droplet evaporation causes densification of the particle ensemble to form a spherical aggregate that deposits in a predominantly ballistic manner, with smaller aggregates forming denser films. If the droplet evaporation lifetime is altered for the aggregates to be partially wet upon impacting the substrate, the subsequent rapid evaporation of the remaining solvent on the substrate leads to formation of films with high interconnectivity. Films formed by the electrospray technique have large-scale uniformity and their structure is independent of thickness. The interpretation of the observed morphologies in terms of Peclet number and Damkhöler number provides a conceptual framework for a rational design of film structures as required by many applications.

Copyright © 2017 American Association for Aerosol Research     

Self-Assembly of pH-Labile Polymer Nanoparticles for Paclitaxel Prodrug Delivery: Formulation,Characterization, and Evaluation

The efficacy of paclitaxel (PTX) is limited due to its poor solubility, poor bioavailability, and acquired drug resistance mechanisms. Designing paclitaxel prodrugs can improve its anticancer activity and enable formulation of nanoparticles. Overall, the aim of this work is to improve the potency of paclitaxel with prodrug synthesis, nanoparticle formation, and synergistic formulation with lapatinib. Specifically, we improve potency of paclitaxel by conjugating it to α-tocopherol (vitamin E) to produce a hydrophobic prodrug (Pro); this increase in potency is indicated by the 8-fold decrease in half maximal inhibitory concentration (IC₅₀) concentration in ovarian cancer cell line, OVCA-432, used as a model system. The efficacy of the paclitaxel prodrug was further enhanced by encapsulation into pH-labile nanoparticles using Flash NanoPrecipitation (FNP), a rapid, polymer directed self-assembly method. There was an 1100-fold decrease in IC₅₀ concentration upon formulating the prodrug into nanoparticles. Notably, the prodrug formulations were 5-fold more potent than paclitaxel nanoparticles. Finally, the cytotoxic effects were further enhanced by co-encapsulating the prodrug with lapatinib (LAP). Formulating the drug combination resulted in synergistic interactions as indicated by the combination index (CI) of 0.51. Overall, these results demonstrate this prodrug combined with nanoparticle formulation and combination therapy is a promising approach for enhancing paclitaxel potency.     

PREPARATION OF ZINC OXIDE NANOPARTICLE VIA UNIFORM PRECIPITATION METHOD AND ITS SURFACE MODIFICATION BY METHACRYLOXYPROPYLTRIMETHOXYSILANE

Zinc oxide nanoparticles were prepared by uniform precipitation using urea hydrolysis. The ZnO precursor was slowly deposited from aqueous solution. Anionic surfactant was added into solution to block ZnO crystal growth and its agglomeration. Then ZnO nanoparticles were synthesized by the calcination of the precursor at high temperature. Transmission electron microscope (TEM) observation and particle size analyzer demonstrated that the ZnO nanoparticle exhibited nearly spheric shape with 10-40 nm particle size. The surface of the ZnO nanoparticle was modified by methacryloxypropyltrimethoxysilane (MPS). FT-IR (Fourier transform-infrared spectrophotometry) and XPS (X-ray photoelectron spectrophotometry) revealed that MPS was grafted onto the zinc oxide nanoparticle. XRD (X-ray diffraction) showed that the ZnO nanoparticle was a hexagonal crystal with a perfect crystalline structure, and its crystalline morphology was not altered through surface modification. The activation index (AI) of the modified ZnO nanoparticle was measured. It was found that the surface of the ZnO nanoparticle was changed from hydrophilicity into hydrophobicity via surface modification, implying the enhancement of its compatibility with organic polymers. FE-SEM (field scanning electron microscopy) showed that the modified ZnO nanoparticles were homogeneously dispersed in PVC matrices. Consequently, ZnO nanoparticles were integrated with PVC matrices by the grafting organic molecule.     

De-agglomeration of hydrophobic and hydrophilic silica nano-powders in a high shear mixer

The effect of energy density, pH and solid concentration on kinetics of de-agglomeration of hydrophobic silica nano-powder in a high shear mixer and on the rheology of resulting suspensions was investigated and compared with de-agglomeration kinetics and rheology of the suspension of hydrophilic silica nano-powder. In both types of nano-powders large aggregates were broken by fracture and erosion. In hydrophobic nano-powder erosion was more pronounced whilst in hydrophilic nano-powder erosion followed initial fracture of large aggregates. At sufficiently high energy input both hydrophobic and hydrophilic aggregates were broken into nano-aggregates but, even at the highest energy input, those nano-aggregates could not have been broken into single nano-particles. Rheology of the suspensions of hydrophobic nano-aggregates strongly depends on pH and on solid concentration whilst rheology of suspensions of hydrophilic nano-powder is rather weakly dependent on those parameters.     

Synthesis of ultra fine particles by plasma transferred arc: Influence of anode material on particle properties

There is a great deal of interest today in the special properties of nanoparticles and their potential applications. Gas-phase process, although having some drawbacks, has the largest control possibilities and is therefore the method chosen here. The size of the primary particles depends on the temperature/time history and material properties. Further growth of the particles strongly depends on the properties of the flow into which they are imbedded.

In the current work, a transferred arc is used to produce nanometric particles from the condensation of metallic vapours obtained by controlled evaporation of the anode material, which becomes the solid precursor of the synthesis. As all types of anode materials would be used, depending of the nature of the desired particles, this technique requires a good control of the heat transfer and its application time to a given anode location, as well as the separation of evaporation/ nucleation-growth steps. That is why a new and original experimental set-up was built in order to control vapour production and its thermal history.

Experiments showed that the heat transfer at the anode precursor strongly depends on the cold boundary layer (CBL) properties close to the anode. For adequate parameters, it becomes possible to generate either diffuse or constricted stable arc root, and so to control vapour production. Orientation and so dissociation of evaporation and nucleation events is also achieved by tilting the angle between the jet issued from the cathode and the anode. The vapours produced are then naturally entrained towards a temperature controlled zone, where they are collected onto a water cooled substrate. It thus becomes possible to control the residence time and the thermal vapour history of the particles. Whereas aluminium oxide particles synthesized are clearly nanoparticle chain aggregates, iron oxides particles are spherical, in the micrometric range and no aggregates or agglomerates are visible. These experiments show that particle morphology, size and shape, for given working parameters, strongly depend on the properties of the material to be vaporized.