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Several previous studies have shown that when a cell that has taken up nanoparticles divides, the nanoparticles are inherited by the two daughter cells in an asymmetrical fashion, with one daughter cell receiving more nanoparticles than the other. This interesting observation is typically demonstrated either indirectly using mathematical modelling of high-throughput experimental data or more directly by imaging individual cells as they divide. Here we suggest that measurements of the coefficient of variation (standard deviation over mean) of the number of nanoparticles per cell over the cell population is another means of assessing the degree of asymmetry. Using simulations of an evolving cell population, we show that the coefficient of variation is sensitive to the degree of asymmetry and note its characteristic evolution in time. As the coefficient of variation is readily measurable using high-throughput techniques, this should allow a more rapid experimental assessment of the degree of asymmetry.

Drug delivery using nano-sized carriers holds tremendous potential for curing a range of diseases. The internalisation of nanoparticles by cells, however, remains poorly understood, restricting the possibility for optimising entrance into target cells, avoiding off-target cells and evading clearance. The majority of nanoparticle cell uptake studies have been performed in the presence of only the particle of interest; here, we instead report measurements of uptake when the cells are exposed to two different types of nanoparticles at the same time. We used carboxylated polystyrene nanoparticles of two different sizes as a model system and exposed them to HeLa cells in the presence of a biomolecular corona. Using flow cytometry, we quantify the uptake at both average and individual cell level. Consistent with previous literature, we show that uptake of the larger particles is impeded in the presence of competing smaller particles and, conversely, that uptake of the smaller particles is promoted by competing larger particles. While the mechanism(s) underlying these observations remain(s) undetermined, we are partly able to restrain the likely possibilities. In the future, these effects could conceivably be used to enhance uptake of nano-sized particles used for drug delivery, by administering two different types of particles at the same time.

Purpose: An electronic version of the Dosepak[R] (EDP) which records date and time of dosing events has been developed to monitor adherence to medication packaged in blisters. This study aimed to evaluate its usability and acceptance and to monitor dose-taking adherence for optimal implementation in future clinical trials and practice. Methods: Healthy volunteers aged over 18 years were asked to dispense placebo tablets twice daily from EDPs equipped with a re-usable electronic module for a total duration of four weeks. Afterwards, subjects were asked to complete an online questionnaire and partake in a short one-on-one interview. The usability of the EDP was assessed using the System Usability Scale (SUS), while dose-taking adherence was monitored by EDP records, pill counting, and self-report. The short interview explored user experiences in more detail. Results: Twenty subjects with median [IQR] age 41.5 [32-49.8] years, 55% female, 45% healthcare professionals, and 20% chronic medication users completed the study and found the EDP easy to use, with a mean [SD] SUS score of 78.0 [11.2]. Median [IQR] dose-taking adherence was 89% [82-95%] based on EDP records, 96.5% [89-100%] based on pill counting, 92% [91-96%] based on self-report, and the levels differed significantly (p < 0.05). Four themes emerged from the interviews: user preference, experience, patient burden, and ideas for improvement. Most participants preferred smaller sized blisters. They found the EDP simple to use and did not see any patient burden for its use in trials or clinical practice. Some reported forgetfulness and suggested reminders built into the blister or sent to their mobile phones. Adequate information or instruction should also be provided for older people and polypharmacy patients. Conclusion: EDP had good perceived usability, was well accepted, and differed significantly from other adherence measurement methods. This study provides input to further guide scale-up of the blister packages. Keywords: compliance, digital health, e-health, patient preference, real-time monitoring, smart packaging

Nanoparticles in contact with the biological environment adsorb a layer of biomolecules, which forms the biological identity of the particles. This Review outlines the concepts of the nanoparticle corona and how it interacts with biological systems, and assesses the critical problems to be resolved. The search for understanding the interactions of nanosized materials with living organisms is leading to the rapid development of key applications, including improved drug delivery by targeting nanoparticles, and resolution of the potential threat of nanotechnological devices to organisms and the environment. Unless they are specifically designed to avoid it, nanoparticles in contact with biological fluids are rapidly covered by a selected group of biomolecules to form a corona that interacts with biological systems. Here we review the basic concept of the nanoparticle corona and its structure and composition, and highlight how the properties of the corona may be linked to its biological impacts. We conclude with a critical assessment of the key problems that need to be resolved in the near future.

Nanoparticles are considered a primary vehicle for targeted therapies because they can pass biological barriers and enter and distribute within cells by energy-dependent pathways 1 , 2 , 3 . So far, most studies have shown that nanoparticle properties, such as size 4 , 5 , 6 and surface 7 , 8 , can influence how cells internalize nanoparticles. Here, we show that uptake of nanoparticles by cells is also influenced by their cell cycle phase. Although cells in different phases of the cell cycle were found to internalize nanoparticles at similar rates, after 24 h the concentration of nanoparticles in the cells could be ranked according to the different phases: G2/M > S > G0/G1. Nanoparticles that are internalized by cells are not exported from cells but are split between daughter cells when the parent cell divides. Our results suggest that future studies on nanoparticle uptake should consider the cell cycle, because, in a cell population, the dose of internalized nanoparticles in each cell varies as the cell advances through the cell cycle. Cells in different phases of the cell-division cycle accumulate different amounts of nanoparticles, suggesting that biological and toxicological studies of nanoparticles should take into account the cell cycle.

Nanoparticles in a biological milieu are known to form a sufficiently long-lived and well-organized ‘corona’ of biomolecules to confer a biological identity to the particle. Because this nanoparticle–biomolecule complex interacts with cells and biological barriers, potentially engaging with different biological pathways, it is important to clarify the presentation of functional biomolecular motifs at its interface. Here, we demonstrate that by using antibody-labelled gold nanoparticles, differential centrifugal sedimentation and various imaging techniques it is possible to identify the spatial location of proteins, their functional motifs and their binding sites. We show that for transferrin-coated polystyrene nanoparticles only a minority of adsorbed proteins exhibit functional motifs and the spatial organization appears random, which is consistent, overall, with a stochastic and irreversible adsorption process. Our methods are applicable to a wide array of nanoparticles and can offer a microscopic molecular description of the biological identity of nanoparticles. Using antibody-conjugated gold nanoparticles and a suite of techniques, the spatial location and type of protein binding sites across biomolecular coronas formed on the surface of nanoparticles are identified.

Background Nanoparticles (NPs) are currently used in a wide variety of fields such as technology, medicine and industry. Due to the novelty of these applications and to ensure their success, a precise characterization of the interactions between NPs and cells is essential. Findings The current study explores the uptake of polystyrene NPs by 1321N1 human astrocytoma and A549 human lung carcinoma cell lines. In this work we show for the first time a comparison of the uptake rates of fluorescently labeled carboxylated polystyrene (PS) NPs of different sizes (20, 40 and 100 nm) in two different cell types, keeping the number of NPs per unit volume constant for all sizes. We propose a reliable methodology to control the dose of fluorescently labeled NPs, by counting individual NPs using automated particle detection from 3D confocal microscopy images. The possibility of detecting individual NPs also allowed us to calculate the size of each nanoparticle and compare the fluorescence of single NPs across different sizes, thereby providing a robust platform for normalization of NP internalization experiments as measured by flow cytometry. Conclusions Our findings show that 40 nm NPs are internalized faster than 20 nm or 100 nm particles in both cell lines studied, suggesting that there is a privileged size gap in which the internalization of NPs is higher.

Nanoparticles have been proposed as carriers for drugs, genes and therapies to treat various diseases 1 , 2 . Many strategies have been developed to target nanomaterials to specific or over-expressed receptors in diseased cells, and these typically involve functionalizing the surface of nanoparticles with proteins, antibodies or other biomolecules. Here, we show that the targeting ability of such functionalized nanoparticles may disappear when they are placed in a biological environment. Using transferrin-conjugated nanoparticles, we found that proteins in the media can shield transferrin from binding to both its targeted receptors on cells and soluble transferrin receptors. Although nanoparticles continue to enter cells, the targeting specificity of transferrin is lost. Our results suggest that when nanoparticles are placed in a complex biological environment, interaction with other proteins in the medium and the formation of a protein corona 3 , 4 can ‘screen’ the targeting molecules on the surface of nanoparticles and cause loss of specificity in targeting. When placed in a complex biological environment, targeting molecules on the surface of nanoparticles are shielded by surrounding biomolecules and their ability to bind to the targeted receptors on cells is lost.