Nanoparticles in a biological fluid (plasma, or otherwise) associate with a range of biopolymers, especially proteins, organized into the "protein corona" that is associated with the nanoparticle and ...continuously exchanging with the proteins in the environment. Methodologies to determine the corona and to understand its dependence on nanomaterial properties are likely to become important in bionanoscience. Here, we study the long-lived ("hard") protein corona formed from human plasma for a range of nanoparticles that differ in surface properties and size. Six different polystyrene nanoparticles were studied: three different surface chemistries (plain PS, carboxyl-modified, and amine-modified) and two sizes of each (50 and 100 nm), enabling us to perform systematic studies of the effect of surface properties and size on the detailed protein coronas. Proteins in the corona that are conserved and unique across the nanoparticle types were identified and classified according to the protein functional properties. Remarkably, both size and surface properties were found to play a very significant role in determining the nanoparticle coronas on the different particles of identical materials. We comment on the future need for scientific understanding, characterization, and possibly some additional emphasis on standards for the surfaces of nanoparticles.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
. De novo drug design is a computational approach that generates novel molecular structures from atomic building blocks with no a priori relationships. Conventional methods include structure-based ...and ligand-based design, which depend on the properties of the active site of a biological target or its known active binders, respectively. Artificial intelligence, including machine learning, is an emerging field that has positively impacted the drug discovery process. Deep reinforcement learning is a subdivision of machine learning that combines artificial neural networks with reinforcement-learning architectures. This method has successfully been employed to develop novel de novo drug design approaches using a variety of artificial networks including recurrent neural networks, convolutional neural networks, generative adversarial networks, and autoencoders. This review article summarizes advances in de novo drug design, from conventional growth algorithms to advanced machine-learning methodologies and highlights hot topics for further development.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The endogenous transport mechanisms which occur in living organisms have evolved to allow selective transport and processing operate on a scale of tens of nanometers. This presents the possibility of ...unprecedented access for engineered nanoscale materials to organs and sub-cellular locations, materials which may in principle be targeted to precise locations for diagnostic or therapeutic gain. For this reason, nano-architectures could represent a truly radical departure as delivery agents for drugs, genes and therapies to treat a host of diseases. Thus, for active targeting, unlike the case of small molecular drugs where molecular structure has evolved to promote higher physiochemical affinity to specific sites, one aims to exploit these energy dependant endogenous processes. Many active targeting strategies have been developed, but despite this truly remarkable potential, in applications they have met with mixed success to date. This situation may have more to do with our current understanding and integration of knowledge across disciplines, than any intrinsic limitation on the vision itself.
In this review article we suggest that much more fundamental and detailed control of the nanoparticle–biomolecule interface is required for sustained and general success in this field. In the simplest manifestation, pristine nanoparticles in biological fluids act as a scaffold for biomolecules, which adsorb rapidly to the nanoparticles' surface, conferring a new biological identity to the nanoparticles. It is this nanoparticle–biomolecule interface that is ‘read’ and acted upon by the cellular machinery. Moreover, where targeting moieties are grafted onto nanoparticles, they may not retain their function as a result of poor orientation, and structural or conformational disruption. Further surface adsorption of biomolecules from the surrounding environment i.e. the formation of a biomolecule corona may also obscure specific surface recognition. To transfer the remarkable possibilities of nanoscale interactions in biology into therapeutics one may need a more focused and dedicated approach to the understanding of the in situ (in vivo) interface between engineered nanomaedicines and their targets.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
It is now clearly emerging that besides size and shape, the other primary defining element of nanoscale objects in biological media is their long-lived protein (“hard”) corona. This corona may be ...expressed as a durable, stabilizing coating of the bare surface of nanoparticle (NP) monomers, or it may be reflected in different subpopulations of particle assemblies, each presenting a durable protein coating. Using the approach and concepts of physical chemistry, we relate studies on the composition of the protein corona at different plasma concentrations with structural data on the complexes both in situ and free from excess plasma. This enables a high degree of confidence in the meaning of the hard protein corona in a biological context. Here, we present the protein adsorption for two compositionally different NPs, namely sulfonated polystyrene and silica NPs. NP−protein complexes are characterized by differential centrifugal sedimentation, dynamic light scattering, and zeta-potential both in situ and once isolated from plasma as a function of the protein/NP surface area ratio. We then introduce a semiquantitative determination of their hard corona composition using one-dimensional sodium dodecyl sulfate−polyacrylamide gel electrophoresis and electrospray liquid chromatography mass spectrometry, which allows us to follow the total binding isotherms for the particles, identifying simultaneously the nature and amount of the most relevant proteins as a function of the plasma concentration. We find that the hard corona can evolve quite significantly as one passes from protein concentrations appropriate to in vitro cell studies to those present in in vivo studies, which has deep implications for in vitro−in vivo extrapolations and will require some consideration in the future.
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IJS, KILJ, NUK, PNG, UL, UM
Given the persistence of microplastics in the environment and their potential toxicity to ecosystems, understanding of likely microplastic accumulation ‘hotspots’ in rivers is urgently needed. To ...contribute to this challenge, this paper reports results of a microplastic survey from a heavily urbanised catchment, the River Tame and four of its tributaries, which flows through the city of Birmingham, UK. All sediment sampled was found to contain microplastics with an average abundance of 165 particles kg−1. While urban areas generally have a greater abundance of microplastics as compared with rural, there is no simple relationship between microplastic numbers and population density or proximity to wastewater treatment sites. The greatest change in microplastic abundance was due to the presence of a lake along the course of the River Tame—i.e., flow velocities are reduced on entering the lake, which promotes the deposition of fine sediment and potentially microplastics. This suggests that the greatest concentrations of microplastics will not be found in-channel but rather on the floodplain and other low velocity environments such as meander cutoffs. We also identified a new mechanism of microplastic fixation in freshwater environments through ecological engineers, specifically caddisflies, that incorporated microplastics into their casing. These results highlight the need to explore further hydrodynamic and ecological impacts on microplastics fate and transport in rivers.
The mechanism(s) of nanoparticle–cell interactions are still not understood. At present there is little knowledge of the relevant length‐ and timescales for nanoparticle intracellular entry and ...localization within cells, or the cell‐specificity of nanoparticle uptake and localisation. Here, the effect of particle size on the in‐vitro intracellular uptake of model fluorescent carboxyl‐modified polystyrene nanoparticles is investigated in various cell lines. A range of micro‐ and nanoparticles of defined sizes (40 nm to 2 μm) are incubated with a series of cell types, including HeLa and A549 epithelial cells, 1321N1 astrocytes, HCMEC D3 endothelial cells, and murine RAW 264.7 macrophages. Techniques such as confocal microscopy and flow cytometry are used to study particle uptake and subcellular localisation, making significant efforts to ensure reproducibility in a semiquantitative approach. The results indicate that internalization of (nano)particles is highly size‐dependent for all cell lines studied, and the kinetics of uptake for the same type of nanoparticle varies in the different cell types. Interestingly, even cells not specialized for phagocytosis are able to internalize the larger nanoparticles. Intracellular uptake of all sizes of particles is observed to be highest in RAW 264.7 cells (a specialized phagocytic cell line) and the lowest in the HeLa cells. These results suggest that (nano)particle uptake might not follow commonly defined size limits for uptake processes, and highlight the variability of uptake kinetics for the same material in different cell types. These conclusions have important implications for the assessment of the safety of nanomaterials and for the potential biomedical applications of nanoparticles.
Uptake and localization of Texas Red‐labeled, carboxylate‐modified polystyrene nanoparticles are studied comparatively across a panel of cell lines. Internalization of the particles is found to be highly size‐dependent for all cell lines studied, but the uptake kinetics vary across different cell types. Intracellular uptake is found to be highest in RAW 264.7 macrophages and lowest in HeLa cells. The results suggest that (nano)particle uptake may not follow the size limits commonly defined for uptake processes, and highlight the variability of uptake kinetics for the same material in different cell lines, with important implications regarding the safety of nanomaterials and their use in biomedical applications.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Nanotechnology is expected to play a vital role in the rapidly developing field of nanomedicine, creating innovative solutions and therapies for currently untreatable diseases, and providing new ...tools for various biomedical applications, such as drug delivery and gene therapy. In order to optimize the efficacy of nanoparticle (NP) delivery to cells, it is necessary to understand the mechanisms by which NPs are internalized by cells, as this will likely determine their ultimate sub-cellular fate and localisation. Here we have used pharmacological inhibitors of some of the major endocytic pathways to investigate nanoparticle uptake mechanisms in a range of representative human cell lines, including HeLa (cervical cancer), A549 (lung carcinoma) and 1321N1 (brain astrocytoma). Chlorpromazine and genistein were used to inhibit clathrin and caveolin mediated endocytosis, respectively. Cytochalasin A and nocodazole were used to inhibit, respectively, the polymerisation of actin and microtubule cytoskeleton. Uptake experiments were performed systematically across the different cell lines, using carboxylated polystyrene NPs of 40 nm and 200 nm diameters, as model NPs of sizes comparable to typical endocytic cargoes. The results clearly indicated that, in all cases and cell types, NPs entered cells via active energy dependent processes. NP uptake in HeLa and 1321N1 cells was strongly affected by actin depolymerisation, while A549 cells showed a stronger inhibition of NP uptake (in comparison to the other cell types) after microtubule disruption and treatment with genistein. A strong reduction of NP uptake was observed after chlorpromazine treatment only in the case of 1321N1 cells. These outcomes suggested that the same NP might exploit different uptake mechanisms to enter different cell types.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The significance of protein coronas on the biological fates of nanoparticles has been widely recognized. Therefore, the alterations on biological effects caused by protein coronas need systemic study ...and interpretation to design novel safe and efficient nanomedicines. In the present study, we present a comprehensive quantitative analysis of the protein coronas on gold nanorods modified with various surface ligands of different chemical compositions and charges. The design of surface ligands is of utmost importance for the functionalization of nanoparticles, and further, the ligand-induced biological identity determines the fate of nanoparticles in the human body. We found that the surface chemistry influences the composition of the protein corona more profoundly than surface charge. Since the first and most important challenge for administrated nanomedicines is navigating the interaction with macrophages, we further investigated how the surface chemistry-induced specific protein corona affects the phagocytosis and immune responses of macrophages exposed to the corona–nanoparticle complexes. Our results reveal that the protein corona alters the internalization pathways of gold nanorods by macrophages via the interactions of the predominant coronal proteins with specific receptors on the cell membrane. The cytokine secretion profile of macrophages is also highly dependent on the adsorption pattern of the protein corona. The more abundant proteins involved in immune responses, such as acute phase, complement, and tissue leakage proteins, present in the acquired nanoparticle corona, the more macrophage interleukin-1β (IL-1β) released is stimulated. The ligand–protein corona composition-immune response coefficient analysis may serve next-generation nanomedicines with high efficiency and good safety for better clinical translation.
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IJS, KILJ, NUK, PNG, UL, UM
Microplastics (MPs) have been widely detected in the world's water, which may pose a significant threat to the ecosystem as a whole and have been a subject of much attention because their presence ...impacts seas, lakes, rivers, and even the Polar Regions. There have been numerous studies that report direct adverse effects on marine organisms, but only a few have explored their ecological effects on freshwater organisms. In this field, there is still a lack of a systematic overview of the toxic effects and mechanisms of MPs on aquatic organisms, as well as a consistent understanding of the potential ecological consequences. This review describes the fate and impact on marine and freshwater aquatic organisms. Further, we examine the toxicology of MPs in order to uncover the relationship between aquatic organism responses to MPs and ecological disorders. In addition, an overview of the factors that may affect the toxicity effects of MPs on aquatic organisms was presented along with a brief examination of their identification and characterization. MPs were discussed in terms of their physicochemical properties in relation to their toxicological concerns regarding their bioavailability and environmental impact. This paper focuses on the progress of the toxicological studies of MPs on aquatic organisms (bacteria, algae, Daphnia, and fish, etc.) of different trophic levels, and explores its toxic mechanism, such as behavioral alternations, metabolism disorders, immune response, and poses a threat to the composition and stability of the ecosystem. We also review the main factors affecting the toxicity of MPs to aquatic organisms, including direct factors (polymer types, sizes, shapes, surface chemistry, etc.) and indirect factors (persistent organic pollutants, heavy metal ions, additives, and monomer, etc.), and the future research trends of MPs ecotoxicology are also pointed out. The findings of this study will be helpful in guiding future marine and freshwater rubbish studies and management strategies.
•Review of the toxicological studies of MPs on aquatic organisms is presented.•MPs toxicity factors are also summarized.•MPs ecotoxicology research trends are also discussed.•An introduction to MPs in aquatic samples and their identification and characterization.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Due to their ultra-small size, nanoparticles (NPs) have distinct properties compared with the bulk form of the same materials. These properties are rapidly revolutionizing many areas of medicine and ...technology. NPs are recognized as promising and powerful tools to fight against the human brain diseases such as multiple sclerosis or Alzheimer's disease. In this review, after an introductory part on the nature of protein fibrillation and the existing approaches for its investigations, the effects of NPs on the fibrillation process have been considered. More specifically, the role of biophysicochemical properties of NPs, which define their affinity for protein monomers, unfolded monomers, oligomers, critical nuclei, and other prefibrillar states, together with their influence on protein fibrillation kinetics has been described in detail. In addition, current and possible-future strategies for controlling the desired effect of NPs and their corresponding effects on the conformational changes of the proteins, which have significant roles in the fibrillation process, have been presented.
Nanoparticles are recognized as promising and powerful tools to fight against the human brain diseases such as Alzheimer's disease. According to their physicochemical properties, nanoparticles may have different effects on the fibrillation of amyloid beta, which is the main foundation of Alzheimer's disease.
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