A nanoinformatics decision support tool for the virtual screening of gold nanoparticle cellular association using protein corona fingerprints

The increasing use of nanoparticles (NPs) in a wide range of consumer and industrial applications has necessitated significant effort to address the challenge of characterizing and quantifying the underlying nanostructure – biological response relationships to ensure that these novel materials can be exploited responsibly and safely. Such efforts demand reliable experimental data not only in terms of the biological dose-response, but also regarding the physicochemical properties of the NPs and their interaction with the biological environment. The latter has not been extensively studied, as a large surface to bind biological macromolecules is a unique feature of NPs that is not relevant for chemicals or pharmaceuticals, and thus only limited data have been reported in the literature quantifying the protein corona formed when NPs interact with a biological medium and linking this with NP cellular association/uptake. In this work we report the development of a predictive model for the assessment of the biological response (cellular association, which can include both internalized NPs and those attached to the cell surface) of surface-modified gold NPs, based on their physicochemical properties and protein corona fingerprints, utilizing a dataset of 105 unique NPs. Cellular association was chosen as the end-point for the original experimental study due to its relevance to inflammatory responses, biodistribution, and toxicity in vivo. The validated predictive model is freely available online through the Enalos Cloud Platform (http://enalos.insilicotox.com/NanoProteinCorona/) to be used as part of a regulatory or NP safe-by-design decision support system. This online tool will allow the virtual screening of NPs, based on a list of the significant NP descriptors, identifying those NPs that would warrant further toxicity testing on the basis of predicted NP cellular association.</p

Pharmacokinetic Characteristics of Nebulized Colistimethate Sodium Using Two Different Types of Nebulizers in Critically Ill Patients with Ventilator-Associated Respiratory Infections

Colistin pharmacokinetics; Critically ill; Inhaled colistinFarmacocinética de la colistina; Enfermo crítico; Colistina inhaladaFarmacocinètica de la colistina; Malalt crític; Colistina inhaladaBackground: Rising antimicrobial resistance has led to a revived interest in inhaled colistin treatment in the critically ill patient with ventilator-associated respiratory infection (VARI). Nebulization via vibrating mesh nebulizers (VMNs) is considered the current standard-of-care, yet the use of generic jet nebulizers (JNs) is more widespread. Few data exist on the intrapulmonary pharmacokinetics of colistin when administered through VMNs, while there is a complete paucity regarding the use of JNs. Methods: In this study, 18 VARI patients who received 2 million international units of inhaled colistimethate sodium (CMS) through a VMN were pharmacokinetically compared with six VARI patients who received the same drug dose through a JN, in the absence of systemic CMS administration. Results: Surprisingly, VMN and JN led to comparable formed colistin exposures in the epithelial lining fluid (ELF) (median (IQR) AUC0–24: 86.2 (46.0–185.9) mg/L∙h with VMN and 91.5 (78.1–110.3) mg/L∙h with JN). The maximum ELF concentration was 10.4 (4.7–22.6) mg/L and 7.4 (6.2–10.3) mg/L, respectively. Conclusions: Based on our results, JN might be considered a viable alternative to the theoretically superior VMN. Therapeutic drug monitoring in the ELF can be advised due to the observed low exposure, high variability, and appreciable systemic absorption.This research was funded by Norma Hellas S.A., grant number 06797/2017, managed by the Special Research Account of the National and Kapodistrian University of Athens (ELKE)

Representing and describing nanomaterials in predictive nanoinformatics

This Review discusses how a comprehensive system for defining nanomaterial descriptors can enable a safe-and-sustainable-by-design concept for engineered nanomaterials. Engineered nanomaterials (ENMs) enable new and enhanced products and devices in which matter can be controlled at a near-atomic scale (in the range of 1 to 100 nm). However, the unique nanoscale properties that make ENMs attractive may result in as yet poorly known risks to human health and the environment. Thus, new ENMs should be designed in line with the idea of safe-and-sustainable-by-design (SSbD). The biological activity of ENMs is closely related to their physicochemical characteristics, changes in these characteristics may therefore cause changes in the ENMs activity. In this sense, a set of physicochemical characteristics (for example, chemical composition, crystal structure, size, shape, surface structure) creates a unique 'representation' of a given ENM. The usability of these characteristics or nanomaterial descriptors (nanodescriptors) in nanoinformatics methods such as quantitative structure-activity/property relationship (QSAR/QSPR) models, provides exciting opportunities to optimize ENMs at the design stage by improving their functionality and minimizing unforeseen health/environmental hazards. A computational screening of possible versions of novel ENMs would return optimal nanostructures and manage ('design out') hazardous features at the earliest possible manufacturing step. Safe adoption of ENMs on a vast scale will depend on the successful integration of the entire bulk of nanodescriptors extracted experimentally with data from theoretical and computational models. This Review discusses directions for developing appropriate nanomaterial representations and related nanodescriptors to enhance the reliability of computational modelling utilized in designing safer and more sustainable ENMs.Peer reviewe

Genetic prediction of ICU hospitalization and mortality in COVID-19 patients using artificial neural networks

There is an unmet need of models for early prediction of morbidity and mortality of Coronavirus disease-19 (COVID-19). We aimed to a) identify complement-related genetic variants associated with the clinical outcomes of ICU hospitalization and death, b) develop an artificial neural network (ANN) predicting these outcomes and c) validate whether complement-related variants are associated with an impaired complement phenotype. We prospectively recruited consecutive adult patients of Caucasian origin, hospitalized due to COVID-19. Through targeted next-generation sequencing, we identified variants in complement factor H/CFH, CFB, CFH-related, CFD, CD55, C3, C5, CFI, CD46, thrombomodulin/THBD, and A Disintegrin and Metalloproteinase with Thrombospondin motifs (ADAMTS13). Among 381 variants in 133 patients, we identified 5 critical variants associated with severe COVID-19: rs2547438 (C3), rs2250656 (C3), rs1042580 (THBD), rs800292 (CFH) and rs414628 (CFHR1). Using age, gender and presence or absence of each variant, we developed an ANN predicting morbidity and mortality in 89.47% of the examined population. Furthermore, THBD and C3a levels were significantly increased in severe COVID-19 patients and those harbouring relevant variants. Thus, we reveal for the first time an ANN accurately predicting ICU hospitalization and death in COVID-19 patients, based on genetic variants in complement genes, age and gender. Importantly, we confirm that genetic dysregulation is associated with impaired complement phenotype.- Pfizer Pharmaceuticals(undefined

Development and In Vitro-Ex Vivo Evaluation of Novel Polymeric Nasal Donepezil Films for Potential Use in Alzheimer&rsquo;s Disease Using Experimental Design

The objective and novelty of the present study is the development and optimization of innovative nasal film of Donepezil hydrochloride (DH) for potential use in Alzheimer&rsquo;s disease. Hydroxypropyl-methyl-cellulose E50 (factor A) nasal films, with Polyethylene glycol 400 as plasticizer (factor B), and Methyl-&beta;-Cyclodextrin, as permeation enhancer (factor C), were prepared and characterized in vitro and ex vivo. An experimental design was used to determine the effects of the selected factors on permeation profile of DH through rabbit nasal mucosa (response 1), and on film flexibility/foldability (response 2). A face centered central composite design with three levels was applied and 17 experiments were performed in triplicate. The prepared films exhibited good uniformity of DH content (90.0 &plusmn; 1.6%&ndash;99.8 &plusmn; 4.9%) and thickness (19.6 &plusmn; 1.9&ndash;170.8 &plusmn; 11.5 &mu;m), storage stability characteristics, and % residual humidity (&lt;3%), as well as favourable swelling and mucoadhesive properties. Response surface methodology determined the optimum composition for flexible nasal film with maximized DH permeation. All selected factors interacted with each other and the effect of these interactions on responses is strongly related to the factor&rsquo;s concentration ratios. Based on these encouraging results, in vivo serum and brain pharmacokinetic study of the optimized nasal film, in comparison to DH oral administration, is ongoing in an animal model

Development of Hybrid DSPC:DOPC:P(OEGMA₉₅₀-DIPAEMA) Nanostructures: The Random Architecture of Polymeric Guest as a Key Design Parameter

Hybrid nanoparticles have gained a lot of attention due to their advantageous properties and versatility in pharmaceutical applications. In this perspective, the formation of novel systems and the exploration of their characteristics not only from a physicochemical but also from a biophysical perspective could promote the development of new nanoplatforms with well-defined features. In the current work, lipid/copolymer bilayers were formed in different lipid to copolymer ratios and examined via differential scanning calorimetry as a preformulation study to decipher the interactions between the biomaterials, followed by nanostructure preparation by the thin-film hydration method. Physicochemical and toxicological evaluations were conducted utilizing light scattering techniques, fluorescence spectroscopy, and MTS assay. 1,2-dioctadecanoyl-sn-glycero-3-phosphocholine (DSPC) and 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) in different weight ratios were the chosen lipids, while a linear random copolymer with pH- and thermoresponsive properties comprised of oligo (ethylene glycol) methyl ether methacrylate (OEGMA) and 2-(diisopropylamino) ethyl methacrylate (DIPAEMA) in different ratios was used. According to our results, non-toxic hybrid nanosystems with stimuli-responsive properties were successfully formulated, and the main parameters influencing their overall performance were the hydrophilic/hydrophobic balance, lipid to polymer ratio, and more importantly the random copolymer topology. Hopefully, this investigation can promote a better understanding of the factors affecting the behavior of hybrid systems

Potential Pharmaceutical Applications of Quercetin in Cardiovascular Diseases

Quercetin, as a member of flavonoids, has emerged as a potential therapeutic agent in cardiovascular diseases (CVDs) in recent decades. In this comprehensive literature review, our goal was a critical appraisal of the pathophysiological mechanisms of quercetin in relation to the classical cardiovascular risk factors (e.g., hyperlipidemia), atherosclerosis, etc. We also assessed experimental and clinical data about its potential application in CVDs. Experimental studies including both in vitro methods and in vivo animal models mainly outline the following effects of quercetin: (1) antihypertensive, (2) hypolipidemic, (3) hypoglycemic, (4) anti-atherosclerotic, and (5) cardioprotective (suppressed cardiotoxicity). From the clinical point of view, there are human studies and meta-analyses implicating its beneficial effects on glycemic and lipid parameters. In contrast, other human studies failed to demonstrate consistent favorable effects of quercetin on other cardiometabolic risk factors such as MS, obesity, and hypertension, underlying the need for further investigation. Analyzing the reason of this inconsistency, we identified significant drawbacks in the clinical trials’ design, while the absence of pharmacokinetic/pharmacodynamic tests prior to the studies attenuated the power of clinical results. Therefore, additional well-designed preclinical and clinical studies are required to examine the therapeutic mechanisms and clinical efficacy of quercetin in CVDs