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Background The lung epithelial tissue barrier represents the main portal for entry of inhaled nanoparticles (NPs) into the systemic circulation. Thus great efforts are currently being made to determine adverse health effects associated with inhalation of NPs. However, to date very little is known about factors that determine the pulmonary translocation of NPs and their subsequent distribution to secondary organs. Methods A novel two-step approach to assess the biokinetics of inhaled NPs is presented. In a first step, alveolar epithelial cellular monolayers (CMLs) at the air-liquid interface (ALI) were exposed to aerosolized NPs to determine their translocation kinetics across the epithelial tissue barrier. Then, in a second step, the distribution to secondary organs was predicted with a physiologically based pharmacokinetic (PBPK) model. Monodisperse, spherical, well-characterized, negatively charged gold nanoparticles (AuNP) were used as model NPs. Furthermore, to obtain a comprehensive picture of the translocation kinetics in different species, human (A549) and mouse (MLE-12) alveolar epithelial CMLs were exposed to ionic gold and to various doses ( i.e., 25, 50, 100, 150, 200 ng/cm 2 ) and sizes ( i.e., 2, 7, 18, 46, 80 nm) of AuNP, and incubated post-exposure for different time periods ( i.e., 0, 2, 8, 24, 48, 72 h). Results The translocation kinetics of the AuNP across A549 and MLE-12 CMLs was similar. The translocated fraction was (1) inversely proportional to the particle size, and (2) independent of the applied dose (up to 100 ng/cm 2 ). Furthermore, supplementing the A549 CML with two immune cells, i.e., macrophages and dendritic cells, did not significantly change the amount of translocated AuNP. Comparison of the measured translocation kinetics and modeled biodistribution with in vivo data from literature showed that the combination of in vitro and in silico methods can accurately predict the in vivo biokinetics of inhaled/instilled AuNP. Conclusion Our approach to combine in vitro and in silico methods for assessing the pulmonary translocation and biodistribution of NPs has the potential to replace short-term animal studies which aim to assess the pulmonary absorption and biodistribution of NPs, and to serve as a screening tool to identify NPs of special concern.

Background Platinum-based anticancer drugs are widely used in the chemotherapy of human neoplasms. The major obstacle for the clinical use of this class of drugs is the development of resistance and toxicity. It is therefore very important to understand the chemical properties, transport and metabolic pathways and mechanism of actions of these compounds. There is a large body of evidence that therapeutic and toxic effects of platinum drugs on cells are not only a consequence of covalent adducts formation between platinum complexes and DNA but also with RNA and many proteins. These processes determine molecular mechanisms that underlie resistance to platinum drugs as well as their toxicity. Increased expression levels of various transporters and increased repair of platinum-DNA adducts are both considered as the most significant processes in the development of drug resistance. Functional genomics has an increasing role in predicting patients' responses to platinum drugs. Genetic polymorphisms affecting these processes may play an important role and constitute the basis for individualized approach to cancer therapy. Similar processes may also influence therapeutic potential of nonplatinum metal compounds with anticancer activity. Conclusions Cisplatin is the most frequently used platinum based chemotherapeutic agent that is clinically proven to combat different types of cancers and sarcomas.

Nanoparticles have potential applications in diagnostics, imaging, gene and drug delivery and other types of therapy. Iron oxide nanoparticles, gold nanoparticles and quantum dots have all generated substantial interest and their properties and applications have been thoroughly studied. Yet, metal-containing particles raise biodistribution and toxicity concerns because they can be quickly cleared from the blood by the reticuloendothelial system and can remain in organs, such as the liver and spleen, for prolonged periods of time. Design considerations, such as size, shape, surface coating and dosing, can be manipulated to prolong blood circulation and enhance treatment efficacy, but nonspecific distribution has thus far been unavoidable. Renal excretion of nanoparticles is possible and is size dependent, but the need to incorporate coatings to particles for increased circulation can hinder such excretion. Further long-term studies are needed because recent work has shown varying degrees of in vivo toxicity as well as varying levels of nanoparticle excretion over time. The interaction of these particles with immune cells and their effect on the innate and adaptive immune response also needs further characterization. Finally, more systematic in vitro approaches are needed to both guide in vivo work and better correlate nanoparticle properties to their biological effects.

Aquaporins (AQPs) are membrane channels that conduct water and small solutes such as glycerol and are involved in many physiological functions. Aquaporin-based modulator drugs are predicted to be of broad potential utility in the treatment of several diseases. Until today few AQP inhibitors have been described as suitable candidates for clinical development. Here we report on the potent inhibition of AQP3 channels by gold(III) complexes screened on human red blood cells (hRBC) and AQP3-transfected PC12 cells by a stopped-flow method. Among the various metal compounds tested, Auphen is the most active on AQP3 (IC(50) = 0.8±0.08 µM in hRBC). Interestingly, the compound poorly affects the water permeability of AQP1. The mechanism of gold inhibition is related to the ability of Au(III) to interact with sulphydryls groups of proteins such as the thiolates of cysteine residues. Additional DFT and modeling studies on possible gold compound/AQP adducts provide a tentative description of the system at a molecular level. The mapping of the periplasmic surface of an homology model of human AQP3 evidenced the thiol group of Cys40 as a likely candidate for binding to gold(III) complexes. Moreover, the investigation of non-covalent binding of Au complexes by docking approaches revealed their preferential binding to AQP3 with respect to AQP1. The high selectivity and low concentration dependent inhibitory effect of Auphen (in the nanomolar range) together with its high water solubility makes the compound a suitable drug lead for future in vivo studies. These results may present novel metal-based scaffolds for AQP drug development.

Surface-enhanced Raman spectroscopy (SERS) is a good candidate for the development of fast and easy-to-use diagnostic tools, possibly used on biofluids in point-of-care or screening tests. In particular, label-free SERS spectra of blood serum and plasma, two biofluids widely used in diagnostics, could be used as a metabolic fingerprinting approach for biomarker discovery. This study aims at a systematic evaluation of SERS spectra of blood serum and plasma, using various Ag and Au aqueous colloids, as SERS substrates, in combination with three excitation lasers of different wavelengths, ranging from the visible to the near-infrared. The analysis of the SERS spectra collected from 20 healthy subjects under a variety of experimental conditions revealed that intense and repeatable spectra are quickly obtained only if proteins are filtered out from samples, and an excitation in the near-infrared is used in combination with Ag colloids. Moreover, common plasma anticoagulants such as EDTA and citrate are found to interfere with SERS spectra; accordingly, filtered serum or heparin plasma are the samples of choice, having identical SERS spectra. Most bands observed in SERS spectra of these biofluids are assigned to uric acid, a metabolite whose blood concentration depends on factors such as sex, age, therapeutic treatments, and various pathological conditions, suggesting that, even when the right experimental conditions are chosen, great care must be taken in designing studies with the purpose of developing diagnostic tests.

A molecularly imprinted polymer (MIP) was developed for the electrochemical determination of the antiviral drug sofosbuvir (SOF). The MIP was obtained by polymerization of p-aminothiophenol (p-ATP) on N,S co-doped graphene quantum dots (N,S@GQDs) in the presence of gold nanoparticles to form gold-sulfur covalent network. The presence of quantum dots improves the electron transfer rate, enhances surface activity and amplifies the signal. The nanocomposites were characterized by FTIR, TEM, EDX, and SEM. The electrochemical performance of the electrode was investigated by differential pulse voltammetry and cyclic voltammetry. The sensor uses hexacyanoferrate as the redox probe and is best operated at a potential of around 0.36 V vs. Ag/AgCl. It has a linear response over the concentration range of 1–400 nM SOF, with a detection limit of 0.36 nM. Other features include high selectivity, good reproducibility and temporal stability. The sensor was applied to the determination of SOF in spiked human plasma. Graphical abstract Novel sofosbuvir imprinted p-ATP polymer was synthesized by the aid of gold nanoparticles on N,S co-doped graphene quantum dots as a good conductive support. The imprinted polymer was used for detection of sofosbuvir in real samples by using the ferri/ferrocyanide redox probe.

Background: In May 2010, a team of national and international organizations was assembled to investigate children's deaths due to lead poisoning in villages in northwestern Nigeria. Objectives: Our goal was to determine the cause of the childhood lead poisoning outbreak, investigate risk factors for child mortality, and identify children < 5 years of age in need of emergency chelation therapy for lead poisoning. Methods: We administered a cross-sectional, door-to-door questionnaire in two affected villages, collected blood from children 2-59 months of age, and obtained soil samples from family compounds. Descriptive and bivariate analyses were performed with survey, blood lead, and environmental data. Multivariate logistic regression techniques were used to determine risk factors for childhood mortality. Results: We surveyed 119 family compounds. Of 463 children < 5 years of age, 118 (25%) had died in the previous year. We tested 59% (204/345) of children < 5 years of age, and all were lead poisoned (≥ 10 μg/dL); 97% (198/204) of children had blood lead levels (BLLs) ≥ 45 μg/dL, the threshold for initiating chelation therapy. Gold ore was processed inside two-thirds of the family compounds surveyed. In multivariate modeling, significant risk factors for death in the previous year from suspected lead poisoning included the age of the child, the mother's work at ore-processing activities, community well as primary water source, and the soil lead concentration in the compound. Conclusion: The high levels of environmental contamination, percentage of children < 5 years of age with elevated BLLs (97%, > 45 μg/dL), and incidence of convulsions among children before death (82%) suggest that most of the recent childhood deaths in the two surveyed villages were caused by acute lead poisoning from gold ore–processing activities. Control measures included environmental remediation, chelation therapy, public health education, and control of mining activities.

The blood-brain barrier prevents the entry of many therapeutic agents into the brain. Various nanocarriers have been developed to help agents to cross this barrier, but they all have limitations, with regard to tissue-selectivity and their ability to cross the endothelium. This study investigated the potential for 4 nm coated gold nanoparticles to act as selective carriers across human brain endothelium and subsequently to enter astrocytes. The transfer rate of glucose-coated gold nanoparticles across primary human brain endothelium was at least three times faster than across non-brain endothelia. Movement of these nanoparticles occurred across the apical and basal plasma membranes via the cytosol with relatively little vesicular or paracellular migration; antibiotics that interfere with vesicular transport did not block migration. The transfer rate was also dependent on the surface coating of the nanoparticle and incubation temperature. Using a novel 3-dimensional co-culture system, which includes primary human astrocytes and a brain endothelial cell line hCMEC/D3, we demonstrated that the glucose-coated nanoparticles traverse the endothelium, move through the extracellular matrix and localize in astrocytes. The movement of the nanoparticles through the matrix was >10 µm/hour and they appeared in the nuclei of the astrocytes in considerable numbers. These nanoparticles have the correct properties for efficient and selective carriers of therapeutic agents across the blood-brain barrier.

Ovarian cancer (OC) must be detected in its early stages when the mortality rate is the lowest to provide patients with the best chance of survival. Lysophosphatidic acid (LPA) is a critical OC biomarker since its levels are elevated across all stages and increase with disease progression. This paper presents an LPA assay based on a thickness shear mode acoustic sensor with dissipation monitoring that involves a new thiol molecule 3-(2-mercaptoethanoxy)propanoic acid (HS-MEG-COOH). HS-MEG-COOH is an antifouling linker that provides (a) antifouling properties for gold substrates and (b) linking ability via its terminal carboxylic acid functional group. The antifouling ability of HS-MEG-COOH was tested in whole human serum. The new molecule was applied to the LPA assay in conjunction with a spacer molecule, 2-(2-mercaptoethoxy)ethan-1-ol (HS-MEG-OH), in a 1:1 v/v ratio. HS-MEG-COOH was covalently linked to gelsolin–actin, a protein complex probe that dissociates due to LPA-binding. LPA was detected in phosphate-buffered saline and undiluted human serum and achieved a low limit of detection (1.0 and 0.7 μM, respectively) which was below the concentration of LPA in healthy individuals. The antifouling properties of HS-MEG-COOH and the detection of LPA demonstrate the ability of the sensor to successfully identify the early-stage OC biomarker in undiluted human serum.

An exciting and emerging field in nanomedicine involves the use of gold nanoparticles (AuNPs) in the preclinical development of new strategies for the treatment and diagnosis of brain-related diseases such as neurodegeneration and cerebral tumors. The treatment of many brain-related disorders with AuNPs, which possess useful physical properties, is limited by the blood-brain barrier (BBB). The BBB highly regulates the substances that can permeate into the brain. Peptides and proteins may represent promising tools to improve the delivery of AuNPs to the central nervous system (CNS). In this review, we summarize the potential applications of AuNPs to CNS disorders, discuss different strategies based on the use of peptides or proteins to improve the delivery of AuNPs to the brain, and examine the intranasal administration route, which bypasses the BBB. We also analyze the potential neurotoxicity of AuNPs and the perspectives and new challenges concerning the use of peptides and proteins to enhance the delivery of AuNPs to the brain. The majority of the work described in this review is in a preclinical stage of experimentation, or in select cases, in clinical trials in humans. We note that the use of AuNPs still requires substantial study before being translated into human applications. However, for further clinical research, the issues related to the potential use of AuNPs must be analyzed.