Antiviral Properties of Streptomyces tuirus DBZ39 Mediated Gold Nanoparticles Against Bluetongue virus.

<b>Background and Objective:</b> The proposed study involves the approach from the point of anti-viral activity of gold nanoparticles against the <i>Bluetongue virus</i>. Among viral diseases, Bluetongue is regarded as an economically scouring disease. Neither a vaccine nor an antiviral drug is available for the prevention or treatment of this disease. The antiviral activity of gold nanoparticles synthesized by a novel isolate of <i>Streptomyces tuirus</i> DBZ39 is the breakthrough of the study. <i>Streptomyces tuirus </i>DBZ39, a novel isolate obtained from alkaline soil was proved to be efficient actinomycetes, for the extracellular synthesis of gold nanoparticles. <b>Materials and Methods:</b> An upstream bioprocess was optimized and developed for the synthesis of controlled size gold nanoparticles with solitary mono dispersal pattern in aurum chloride solution. The characterization and confirmation of gold nanoparticles were illustrated by Scanning Electron Microscopy (SEM), Transmission Electron Microscopy (TEM), Energy Dispersive X-ray Analysis (EDAX) and Fourier Transmission Infrared Radiation Analysis (FTIR). <b>Results:</b> Biomass size of 3 g, substrate concentration of 1 mM, pH of 8.5 and temperature of 45°C were observed as optimum conditions for the synthesis of 15-24 nm size gold nanoparticles. The <i>Bluetongue virus</i> (BTV) which belongs to the genus Orbivirus in the family Reoviridae with 26 serotypes is an etiological agent of infectious and non-contagious Bluetongue disease of main sheep and several other domestic animals. <b>Conclusion:</b> Gold nanoparticles for the 1st time, at a higher concentration of 1:64 dilutions revealed a very promising and novel antiviral property against the <i>Bluetongue virus</i>.

Quality by design (QbD) in the formulation and optimization of liquid crystalline nanoparticles (LCNPs): A risk based industrial approach.

The intersection of lipid-based nanoparticles and lyotropic liquid crystals has provided a novel type of nanocarrier system known as 'lipid-based lyotropic liquid crystals' or 'liquid crystalline nanoparticles' (LCNPs). The unique advantages and immense popularity of LCNPs can be exploited in a better way if the formulation of LCNPs is done using the approach of quality by design (QbD). QbD is a systematic method that can be utilized in formulation development. When QbD is applied to LCNPs formulation, it will proffer many unique advantages, such as better product and process understanding, the flexibility of process within the design space, implementation of more effective and efficient control strategies, easy transfer from bench to bedside, and more robust product. In this work, the application of QbD in the formulation of LCNPs has been explored. The elements of QbD, viz. quality target product profile, critical quality attributes, critical material attributes, critical process parameters, quality risk management, design of experiments, and control strategy for the development of LCNPs have been explained in-depth with case studies. The present work will help the reader to understand the nitty-gritties in the application of QbD in the formulation of LCNPs, and provide a base for QbD-driven formulation of LCNPs with a regulatory perspective.

Evaluation of the Physicochemical Properties of the Iron Nanoparticle Drug Products: Brand and Generic Sodium Ferric Gluconate.

Complex iron nanoparticle-based drugs are one of the oldest and most frequently administered classes of nanomedicines. In the US, there are seven FDA-approved iron nanoparticle reference drug products, of which one also has an approved generic drug product (i.e., sodium ferric gluconate (SFG)). These products are indicated for the treatment of iron deficiency anemia and are administered intravenously. On the molecular level, iron nanomedicines are colloids composed of an iron oxide core with a carbohydrate coating. This formulation makes nanomedicines more complex than conventional small molecule drugs. As such, these products are often referred to as nonbiological complex drugs (e.g., by the nonbiological complex drugs (NBCD) working group) or complex drug products (e.g., by the FDA). Herein, we report a comprehensive study of the physiochemical properties of the iron nanoparticle product SFG. SFG is the single drug for which both an innovator (Ferrlecit) and generic product are available in the US, allowing for comparative studies to be performed. Measurements focused on the iron core of SFG included optical spectroscopy, inductively coupled plasma mass spectrometry (ICP-MS), X-ray powder diffraction (XRPD), 57Fe Mössbauer spectroscopy, and X-ray absorbance spectroscopy (XAS). The analysis revealed similar ferric-iron-oxide structures. Measurements focused on the carbohydrate shell comprised of the gluconate ligands included forced acid degradation, dynamic light scattering (DLS), analytical ultracentrifugation (AUC), and gel permeation chromatography (GPC). Such analysis revealed differences in composition for the innovator versus the generic SFG. These studies have the potential to contribute to future quality assessment of iron complex products and will inform on a pharmacokinetic study of two therapeutically equivalent iron gluconate products.

Smart Design of Nanomaterials for Mitochondria-Targeted Nanotherapeutics.

Mitochondria are the powerhouse of cells. They are vital organelles that maintain cellular function and metabolism. Dysfunction of mitochondria results in various diseases with a great diversity of clinical appearances. In the past, strategies have been developed for fabricating subcellular-targeting drug-delivery nanocarriers, enabling cellular internalization and subsequent organelle localization. Of late, innovative strategies have emerged for the smart design of multifunctional nanocarriers. Hierarchical targeting enables nanocarriers to evade and overcome various barriers encountered upon in vivo administration to reach the organelle with good bioavailability. Stimuli-responsive nanocarriers allow controlled release of therapeutics to occur at the desired target site. Synergistic therapy can be achieved using a combination of approaches such as chemotherapy, gene and phototherapy. In this Review, we survey the field for recent developments and strategies used in the smart design of nanocarriers for mitochondria-targeted therapeutics. Existing challenges and unexplored therapeutic opportunities are also highlighted and discussed to inspire the next generation of mitochondrial-targeting nanotherapeutics.

[A new occupational and environmental hazard - nanoplastic]. / Nowe zagrozenie zawodowe i srodowiskowe ­ nanoplastik.

Problems arising from the accumulation of plastic waste in the environment have become global. Appeals to stop the usage of disposable drinking straws or plastic cutlery did not come out without reason - 320 million tons of plastic products are produced annually, of which 40% are disposable items. More and more countries and private enterprises are giving up these types of items in favor of their biodegradable substitutes, e.g., cardboard drinking straws. Plastic waste in the environment is subject to a number of physicochemical interactions and biodegradation in which bacteria are involved. By using synthetic waste, they reduce the size of plastic garbage while increasing its dispersion in the environment. Small plastic particles, invisible to the naked eye, are called nanoplastic. Nanoplastic is not inert to living organisms. Due to its size, it is taken up with food by animals and passed on in the trophic chain. The ability to penetrate the body's barriers through nanoplastic leads to the induction of biological effects with various outcomes. Research studies on the interaction of nanoplastic with living organisms are carried out in many laboratories; however, their number is still a drop in the ocean of the data needed to draw clear-cut conclusions about the impact of nanoplastic on living organisms. There is also no data on the direct exposure to nanoplastic contamination at workplaces, schools and public utilities, standards describing the acceptable concentration of nanoplastic in food products and drinking water, and in vitro tests on nanoparticles other than polystyrene nanoparticles. Complementing the existing data will allow assessing the risks arising from the exposure of organisms to nanoplastic. Med Pr. 2020;71(6):743-56.

Development and optimization of dynamic gelatin/chitosan nanoparticles incorporated with blueberry anthocyanins for milk freshness monitoring.

In this study, we prepared gelatin and chitosan as wall materials, and composites with a controlled release capability in a weak acidic environment were synthesized for loading and protecting anthocyanins. Fourier-transform infrared spectroscopy and scanning electron microscopy were used to assess the properties of the nanoparticles. The loading efficiencies and oxidation resistances of the proposed substances were measured. Under optimal conditions, the anthocyanins exhibited a loading efficiency of 83.81 %, and suitable long-term storage capacity at room temperature with a retention rate of ∼50 % after 15 d. When the nanoparticles were used for detecting the milk freshness, spoiled milk exhibited a reddish color, whereas the color of fresh milk did not change. Moreover, these nanoparticles exhibited a stable chroma in milk for 0-16 h. Therefore, the proposed pH responsive nanoparticles can provide a possibility for the dynamic monitoring of milk quality changes, or provide some reference value for future related research.

Continued Efforts on Nanomaterial-Environmental Health and Safety Is Critical to Maintain Sustainable Growth of Nanoindustry.

Nanotechnology is enjoying an impressive growth and the global nanotechnology industry is expected to exceed US$ 125 billion by 2024. Based on these successes, there are notions that enough is known and efforts on engineered nanomaterial environmental health and safety (nano-EHS) research should be put on the back burner. However, there are recent events showing that it is not the case. The US Food and Drug Administration found ferumoxytol (carbohydrate-coated superparamagnetic iron oxide nanoparticle) for anemia treatment could induce lethal anaphylactic reactions. The European Union will categorize TiO2 as a category 2 carcinogen due to its inhalation hazard and France banned use of TiO2 (E171) in food from January 1, 2020 because of its carcinogenic potential. Although nanoindustry is seemingly in a healthy state, growth could be hindered for the lack of certainty and more nano-EHS research is needed for the sustainable growth of nanoindustry. Herein, the current knowledge gaps and the way forward are elaborated.

Shear-, Sound-, and Light-Sensitive Nanoparticles for Thrombolytic Drug Delivery.

Thrombotic diseases, as potentially induced by blood clots or vascular embolization, frequently occur with high rates of mortalities worldwide. Current drug thrombolysis, a primary clinical therapy, may increase fatal risk of hemorrhage when thrombolysis agents become systemically distributed. Given current thrombolysis limitations, some novel drug delivery systems based on nanoparticles have been recently exploited to achieve a more controlled release of loaded thrombolytic agents, able to respond to environmental changes, and resulting in a safer thrombolysis. In this review, the authors outline and discuss some prominent examples of early and recent thrombolytic agent delivery systems using controlled release by physical stimuli (shear, sound and light). Shear-sensitive systems are designed to exploit the specific biomechanical feature of thrombosis, that is, the increased blood shear stress. Sound- and light-sensitive systems reflect "remote control" of drug release by responding to external ultrasound or light stimulus. These smart thrombolytic drug delivery systems hold promise for more effective and safer future thrombolytic therapy.

Design Considerations and Assays for Hemocompatibility of FDA-Approved Nanoparticles.

Nanoparticles have numerous biomedical applications including, but not limited to, targeted drug delivery, diagnostic imaging, sensors, and implants for a wide range of diseases including cancer, diabetes, heart disease, and tuberculosis. Although the mode of delivery of the nanoparticles depends on the application and the disease, the nanoparticles are often in immediate contact with the systemic circulation either because of intravenous administration or their ability to enter the bloodstream with relative ease or their longer survival time in circulation. Once in circulation, the nanoparticles may elicit unintended hemostatic and inflammatory responses, and hence the design of nanoparticles for therapeutic applications should take broad hemocompatibility concerns into consideration. In this review, we present the principles underlying the structural and functional design of various classes of nanoparticles that are currently approved by the US Food and Drug Administration, categorize these particles based on their interactions with cardiovascular tissues and ensuing adverse events, and also describe various in vitro assays that may be used evaluate their hemocompatibility.

Size matters: the importance of particle size in a newly developed injectable formulation for the treatment of schizophrenia.

One of the challenges with initiating long-acting injectable (LAI) antipsychotic regimens is achieving relevant drug levels quickly. After first injection of the LAI antipsychotic aripiprazole lauroxil (AL), the lag to reaching relevant plasma aripiprazole levels was initially addressed using supplemental oral aripiprazole for 21 days. A 1-day AL initiation regimen using a NanoCrystal® Dispersion formulation of AL (ALNCD; Aristada Initio®) combined with a single 30 mg dose of oral aripiprazole has been developed as an alternative approach. We compared the 1-day AL initiation regimen (ALNCD + 30 mg oral aripiprazole for 1 day) with the 21-day AL initiation regimen (AL + 15 mg/day of oral aripiprazole for 21 days) using kinetic modeling. Observed and modeled data demonstrate that the 1-day AL initiation regimen provides continuous aripiprazole exposure comparable to the 21-day AL initiation regimen. Each component of the 1-day AL initiation regimen (30 mg oral aripiprazole, ALNCD, and AL) contributes to aripiprazole plasma levels at different times, with oral aripiprazole predominating in the first week, then ALNCD and AL over time. In a double-blind, placebo-controlled, phase 1 study in patients with schizophrenia, the 1-day initiation regimen resulted in rapid achievement of relevant plasma aripiprazole levels comparable to those from the 21-day initiation regimen. Safety and tolerability of the 1-day regimen were consistent with the known profile of aripiprazole. Each part of the 1-day initiation regimen, together with AL, is necessary for continuous aripiprazole exposure from treatment initiation until the next regularly scheduled AL injection is administered.

Naked-Eye Readout of Analyte-Induced NIR Fluorescence Responses by an Initiation-Input-Transduction Nanoplatform.

Fluorescence visualization (FV) in the near-infrared (NIR) window promises to break through the signal-to-background ratio (SBR) bottleneck of traditional visible-light-driven FV methods. However, straightforward NIR-FV has not been realized, owing to the lack of methods to readily transduce NIR responses into instrument-free, naked eye-recognizable outputs. Now, an initiation-input-transduction platform comprising a well-designed NIR fluorophore as the signal initiator and lanthanide-doped nanocrystals as the transducer for facile NIR-FV is presented. The analyte-induced off-on NIR signal serves as a sensitizing switch of transducer visible luminescence for naked-eye readout. The design is demonstrated for portable, quantitative detection of phosgene with significantly improved SBR and sensitivity. By further exploration of initiators, this strategy holds promise to create advanced NIR-FV probes for broad sensing applications.

Is "nano safe to eat or not"? A review of the state-of-the art in soft engineered nanoparticle (sENP) formulation and delivery in foods.

With superior physicochemical properties, soft engineered nanoparticles (sENP) (protein, carbohydrate, lipids and other biomaterials) are widely used in foods. The preparation, functionalities, applications, transformations in gastrointestinal (GI) tract, and effects on gut microbiota of sENP directly incorporated for ingestion are reviewed herein. At the time of this review, there is no notable report of safety concerns of these nanomaterials found in the literature. Meanwhile, various beneficial effects have been demonstrated for the application of sENP. To address public perception and safety concerns of nanoscale materials in food, methodologies for evaluation of physiological effects of nanomaterials are reviewed. The combination of these complementary methods will be useful for the establishment of a comprehensive risk assessment system.

Nanoparticle-Based Paramagnetic Contrast Agents for Magnetic Resonance Imaging.

Magnetic resonance imaging (MRI) is a noninvasive medical imaging modality that is routinely used in clinics, providing anatomical information with micron resolution, soft tissue contrast, and deep penetration. Exogenous contrast agents increase image contrast by shortening longitudinal (T 1) and transversal (T 2) relaxation times. Most of the T 1 agents used in clinical MRI are based on paramagnetic lanthanide complexes (largely Gd-based). In moving to translatable formats of reduced toxicity, greater chemical stability, longer circulation times, higher contrast, more controlled functionalisation and additional imaging modalities, considerable effort has been applied to the development of nanoparticles bearing paramagnetic ions. This review summarises the most relevant examples in the synthesis and biomedical applications of paramagnetic nanoparticles as contrast agents for MRI and multimodal imaging. It includes the most recent developments in the field of production of agents with high relaxivities, which are key for effective contrast enhancement, exemplified through clinically relevant examples.

Regulating Nanomedicine at the Food and Drug Administration.

The US Food and Drug Administration (FDA) oversees safety and efficacy of a broad spectrum of medical products (ie, drugs, biologics, and devices) under the auspices of federal legislation and agency regulations and policy. Complex and emerging nanoscale products challenge this regulatory framework and illuminate its shortcomings for combination products that integrate multiple mechanisms of therapeutic action. This article surveys current FDA regulatory structures and nanotechnology-specific guidance, discusses relevant nanomedicine products, and identifies regulatory challenges.

A quality-by-design study to develop Nifedipine nanosuspension: examining the relative impact of formulation variables, wet media milling process parameters and excipient variability on drug product quality attributes.

Wet milling is a multifunctional and the most common method to prepare a drug nanosuspension for improving the bioavailability of poorly water soluble drugs. A suitable way of preparing a high drug-loaded nifedipine nanosuspension using wet stirred media milling was investigated in the present study. Nifedipine, a poorly water soluble drug, was selected as a model drug to enhance its dissolution rate and oral bioavailability by preparing an appropriate crystalline nanosuspension. Process parameters, such as milling media volume, milling speed and milling time, were optimized using the one variable at a time (OVAT) approach. A similar method was used to select an appropriate polymeric stabilizer and a surfactant from different categories of polymeric stabilizers (HPC SL, HPC SSL Soluplus®, Kollidon® VA 64 and HPMC E 15) and surfactants (Poloxamer 407, Kolliphor TPGS and Docusate sodium). A systematic optimization of critical formulation parameters (such as drug concentration, polymer concentration and surfactant concentration) was performed with the aid of the Box-Behnken design. Mean particle size, polydispersity index and zeta potential as critical quality attributes (CQAs) were selected in the design for the evaluation and optimization of the formulation and validation of the improved product. The nifedipine nanosuspension that was prepared using HPC and poloxamer 407 was found to be most stable with the lowest mean particle size as compared with the formulations prepared using other polymeric stabilizers and surfactants. The optimized formulation was further spray-dried and characterized using the Fourier Transform Infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), polarized light microscopy (PLM) and in-vitro dissolution study. Results have shown no interaction between the drug particles and stabilizers, nor a reduction in the crystallinity of drug, nor an increase in the saturation solubility and rapid in vitro dissolution as compared with pure nifedipine crystals. Thus, the current study supports the suitability of the wet stirred media milling method and a combination of HPC SSL and poloxamer 407 as stabilizers for the preparation of nifedipine nanosuspension.

Nano-sized emission from commercially available paints used for indoor surfaces during drying.

Consumers worry about the presence of nano-particles in paints and the risk of exposure. As a result, the paint industry now omits marketing paints as containing nanoparticles. The industry claims that no nanoparticles are released into the indoor environment; this, however, has yet to be documented. In this study, the emission of nano-sized emission from four indoor paints was investigated. The emission was studied for both base and full-pigmented versions of the paints, which consisted of three water-borne acrylic paints and one solvent-borne alkyd paint. All experiments were performed twice in a 6.783 m3 stainless-steel test chamber under standardized conditions (22.98 °C, 50.08% RH, air exchange rate 0.48 h-1). Emissions during the paint-drying period were measured using a TSI Fast Mobility Particle Sizer (FMPS) measuring the number concentration of nano-particles and the size distribution in the range 5.6-560 nm. The results from the solvent-borne paint showed the highest concentration, with a mean concentration of 3.2·105 particles/cm3 and a maximum of 1.4·106 particles/cm3. This paint also had the smallest particle size distribution, with 9.31 nm particles as the most dominant particle size. The results from this study showed that the exposure to nanoparticles for the residents evaluated over a 7 or 28 day period was low and that interior paints are probably not very important when it comes to identifying products that release nano-particles into indoor environments.

Criteria to define a more relevant reference sample of titanium dioxide in the context of food: a multiscale approach.

Titanium dioxide (TiO2) is a transition metal oxide widely used as a white pigment in various applications, including food. Due to the classification of TiO2 nanoparticles by the International Agency for Research on Cancer as potentially harmful for humans by inhalation, the presence of nanoparticles in food products needed to be confirmed by a set of independent studies. Seven samples of food-grade TiO2 (E171) were extensively characterised for their size distribution, crystallinity and surface properties by the currently recommended methods. All investigated E171 samples contained a fraction of nanoparticles, however, below the threshold defining the labelling of nanomaterial. On the basis of these results and a statistical analysis, E171 food-grade TiO2 totally differs from the reference material P25, confirming the few published data on this kind of particle. Therefore, the reference material P25 does not appear to be the most suitable model to study the fate of food-grade TiO2 in the gastrointestinal tract. The criteria currently to obtain a representative food-grade sample of TiO2 are the following: (1) crystalline-phase anatase, (2) a powder with an isoelectric point very close to 4.1, (3) a fraction of nanoparticles comprised between 15% and 45%, and (4) a low specific surface area around 10 m2 g-1.

Nanoparticle standards for immuno-based quantitation of α-synuclein oligomers in diagnostics of Parkinson's disease and other synucleinopathies.

Parkinson's disease (PD) is a neurodegenerative disorder that is characterized by symptoms such as rigor, tremor and bradykinesia. A reliable and early diagnosis could improve the development of early therapeutic strategies before death of dopaminergic neurons leads to the first clinical symptoms. The sFIDA (surface-based fluorescence intensity distribution analysis) assay is a highly sensitive method to determine the concentration of α-synuclein (α-syn) oligomers which are presumably the major toxic isoform of α-syn and potentially the most direct biomarker for PD. Oligomer-based diagnostic tests require standard molecules that closely mimic the native oligomer. This is particularly important for calibration and assessment of inter-assay variation. In this study, we generated a standard in form of α-syn coated silica nanoparticles (α-syn-SiNaPs) that are in the size range of α-syn oligomers and provide a defined number of α-syn epitopes. The preparation of the sFIDA assay was realized on an automated platform to allow handling of high number of samples and reduce the effects of human error. The assay outcome was analyzed by determination of coefficient of variation and linearity for the applied α-syn-SiNaPs concentrations. Additionally, the limit of detection and lower limit of quantification were determined yielding concentrations in the lower femtomolar range.

Physiologically Based Pharmacokinetic (PBPK) Modeling of Pharmaceutical Nanoparticles.

With the great interests in the discovery and development of drug products containing nanoparticles, there is a great demand of quantitative tools for assessing quality, safety, and efficacy of these products. Physiologically based pharmacokinetic (PBPK) modeling and simulation approaches provide excellent tools for describing and predicting in vivo absorption, distribution, metabolism, and excretion (ADME) of nanoparticles administered through various routes. PBPK modeling of nanoparticles is an emerging field, and more than 20 PBPK models of nanoparticles used in pharmaceutical products have been published in the past decade. This review provides an overview of the ADME characteristics of nanoparticles and how these ADME processes are described in PBPK models. Recent advances in PBPK modeling of pharmaceutical nanoparticles are summarized. The major challenges in model development and validation and possible solutions are also discussed.