Conception, synthèse et caractérisation de nouvelles macromolécules branchées biocompatibles pour encapsuler des principes actifs hydrophobes

La vectorisation des médicaments est une approche très prometteuse tant sur le plan médical qu’économique pour la livraison des substances actives ayant une faible biodisponibilité. Dans ce contexte, les polymères en étoile et les dendrimères, macromolécules symétriques et branchées, semblent être les solutions de vectorisation les plus attrayantes. En effet, ces structures peuvent combiner efficacement une stabilité élevée dans les milieux biologiques à une capacité d’encapsulation des principes actifs. Grâce à leur architecture bien définie, ils permettent d’atteindre un très haut niveau de reproductibilité de résultats, tout en évitant le problème de polydispersité. Bien que des nombreuses structures dendritiques aient été proposées ces dernières années, il est cependant à noter que la conception de nouveaux nanovecteurs dendritiques efficaces est toujours d’actualité. Ceci s’explique par des nombreuses raisons telles que celles liées à la biocompatibilité, l’efficacité d’encapsulation des agents thérapeutiques, ainsi que par des raisons économiques. Dans ce projet, de nouvelles macromolécules branchées biocompatibles ont été conçues, synthétisées et évaluées. Pour augmenter leur efficacité en tant qu’agents d’encapsulations des principes actifs hydrophobes, les structures de ces macromolécules incluent un coeur central hydrophobe à base de porphyrine, décanediol ou trioléine modifié et, également, une couche externe hydrophile à base d’acide succinique et de polyéthylène glycol. Le choix des éléments structuraux de futures dendrimères a été basé sur les données de biocompatibilité, les résultats de nos travaux de synthèse préliminaires, ainsi que les résultats de simulation in silico réalisée par une méthode de mécanique moléculaire. Ces travaux ont permis de choisir des composés les plus prometteurs pour former efficacement et d’une manière bien contrôlable des macromolécules polyesters. Ils ont aussi permis d’évaluer au préalable la capacité de futurs dendrimères de capter une molécule médicamenteuse (itraconazole). Durant cette étape, plusieurs nouveaux composés intermédiaires ont été obtenus. L’optimisation des conditions menant à des rendements réactionnels élevés a été réalisée. En se basant sur les travaux préliminaires, l’assemblage de nouveaux dendrimères de première et de deuxième génération a été effectué, en utilisant les approches de synthèse divergente et convergente. La structure de nouveaux composés a été prouvée par les techniques RMN du proton et du carbone 13C, spectroscopie FTIR, UV-Vis, analyse élémentaire, spectrométrie de masse et GPC. La biocompatibilité de produits a été évaluée par les tests de cytotoxicité avec le MTT sur les macrophages murins RAW-262.7. La capacité d’encapsuler les principes actifs hydrophobes a été étudiée par les tests avec l’itraconazole, un antifongique puissant mais peu biodisponible. La taille de nanoparticules formées dans les solutions aqueuses a été mesurée par la technique DLS. Ces mesures ont montré que toutes les structures dendritiques ont tendance à former des micelles, ce qui exclue leurs applications en tant que nanocapsules unimoléculaires. L’activité antifongique des formulations d’itraconazole encapsulé avec les dendrimères a été étudiée sur une espèce d’un champignon pathogène Candida albicans. Ces tests ont permis de conclure que pour assurer l’efficacité du traitement, un meilleur contrôle sur le relargage du principe actif était nécessaire.The drug molecule vectorization is a very promising approach in terms of both medical and economical factors for the delivery of active substances with low bioavailability. In this context, the star polymers and dendrimers, symmetrical and branched macromolecules, seem to be more attractive solutions. Indeed, these structures can effectively combine a high stability in biological media and the ability to encapsulate active ingredients. Thanks to the well-defined architecture, they can achieve a high level of reproducibility of results, while avoiding the problem of polydispersity. In recent years, many dendritic structures have been proposed; however, the design of new effective dendritic nanocarriers is still relevant. This is due to many reasons such as related to biocompatibility, encapsulation efficiency of therapeutic agents, as well as economic reasons. In this project, new branched biocompatible macromolecules were designed, synthesized and evaluated. To increase their effectiveness as encapsulation agents for hydrophobic active principles, the structures of the proposed macromolecules include a hydrophobic central core on the basis of porphyrin, decanediol or modified triolein, and also a hydrophilic outer layer based on succinic acid and polyethylene glycol. The choice of structural elements of future dendrimers was based on the data on their biocompatibility and the results of our preliminary synthesis works, as well as the in silico simulations performed by using the method of molecular mechanics. The preliminary studies allowed for selecting the most promising compounds to effectively form polyesters macromolecules in well controlled manner, as well as to assess in advance the ability of future dendrimers to capture a drug molecule (itraconazole). During this phase, several new intermediates were obtained. The optimization of reaction conditions leading to high yields was performed. Based on the preliminary work, the assembly of new dendrimers of first and second generations was performed, by using the divergent and convergent synthesis approaches. The structures of new compounds were characterized by proton and 13C carbon NMR, FTIR, UV-Vis, elemental analysis, mass spectrometry, and GPC techniques. The biocompatibility of products was evaluated by cytotoxicity tests with MTT on murine RAW 262.7 macrophages. The ability to encapsulate hydrophobic active principles was studied by testing with itraconazole, an antifungal agent with low bioavalability. The size of nanoparticles formed in aqueous solutions was measured by the DLS technique. These measurements showed that all dendritic structures tend to form micelles, which excludes their application as unimolecular nanocapsules. The antifungal activity of itraconazole formulations with dendrimers was studied in a kind of a pathogenic fungus Candida albicans. These tests lead to the conclusion that to ensure the effectiveness of treatment, more control over the release of the active ingredient has been needed

Drug-loaded nanocarriers : passive targeting and crossing of biological barriers

Poor bioavailability and poor pharmacokinetic characteristics are some of the leading causes of drug development failure. Therefore, poorly-soluble drugs, fragile proteins or nucleic acid products may benefit from their encapsulation in nanosized vehicles, providing enhanced solubilisation, protection against degradation, and increased access to pathological compartments. A key element for the success of drug-loaded nanocarriers (NC) is their ability to either cross biological barriers themselves or allow loaded drugs to traverse them to achieve optimal pharmacological action at pathological sites. Depending on the mode of administration, NC may have to cross different physiological barriers in their journey towards their target. In this review, the crossing of biological barriers by passive targeting strategies will be presented for intravenous delivery (vascular endothelial lining, particularly for tumour vasculature and blood-brain barrier targeting), oral administration (gastrointestinal lining) and upper airway administration (pulmonary epithelium). For each specific barrier, background information will be provided on the structure and biology of the tissues involved as well as available pathways for nano-objects or loaded drugs (diffusion and convection through fenestration, transcytosis, tight junction crossing, etc.). The determinants of passive targeting − size, shape, surface chemistry, surface patterning of nanovectors − will be discussed in light of current results. Perspectives on each mode of administration will be presented. The focus will be on polymeric nanoparticles and dendrimers although advances in liposome technology will be also reported as they represent the largest body in the drug delivery literature

Transverse Optical Mode Patterns for an RF Excited Ar-He-Xe Laser

Transverse optical modes for an RF excited Ar-He-Xe laser are studied both experimentally and theoretically. A diffraction model for a waveguide with a nonsaturable gain and refractive index gradients placed between two plane mirrors is formulated. The effects of gain and diffraction index gradients and of diffraction in free space are evaluated for typical experimental conditions. A direct comparison between theoretical mode patterns and experimentally measured ones at distances of 17 and 114 cm from the output mirror demonstrated a satisfactory agreement for various laser wavelengths and gas mixture composition

Study Wetting Coal Dust Fraction of Particles of Surfactant Solutions

Представлены результаты экспериментальных исследований и теоретическое обоснование по смачиванию растворами поверхностно-активных веществ частиц углей фракций малых размеров. На основе физической модели экспериментального опыта по смачиванию частиц угля показано, что в результате измельчений угля от крупных кусков до пылеобразного состояния существенно изменяются структурные и поверхностные свойства угля, что приводит к существенному изменению механических, физико-химических свойств углейThe results of experimental studies and theoretical basis for wetting solutions surfactants coal particles of small size fractions. On the basis of a physical model on experimental experience shows wetting of the coal particles, resulting from pulverized coal lumps pulverized state to substantially change the structural and surface properties of the coal, which leads to a substantial change in the mechanical, physical and chemical properties of coa

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

A multi-country test of brief reappraisal interventions on emotions during the COVID-19 pandemic.

The COVID-19 pandemic has increased negative emotions and decreased positive emotions globally. Left unchecked, these emotional changes might have a wide array of adverse impacts. To reduce negative emotions and increase positive emotions, we tested the effectiveness of reappraisal, an emotion-regulation strategy that modifies how one thinks about a situation. Participants from 87 countries and regions (n = 21,644) were randomly assigned to one of two brief reappraisal interventions (reconstrual or repurposing) or one of two control conditions (active or passive). Results revealed that both reappraisal interventions (vesus both control conditions) consistently reduced negative emotions and increased positive emotions across different measures. Reconstrual and repurposing interventions had similar effects. Importantly, planned exploratory analyses indicated that reappraisal interventions did not reduce intentions to practice preventive health behaviours. The findings demonstrate the viability of creating scalable, low-cost interventions for use around the world

Synthesis and characterization of 3-methyl-6-[(propynyloxy)methyl]-1,4-dioxane-2,5-dione

The number of known asymmetrically substituted hemilactides, important precursors for obtaining regular derivatives of polylactide polymers, is still limited and structural characterization of most of them is incomplete. In the title racemic 1,4-dioxane-2,5-dione derivative, C9H10O5, the hemilactide heterocycle exhibits a twist-boat conformation. The bulkier propynyloxymethyl group is in an axial position with a gauche conformation for the CH2–O–CH2–C segment. In the crystal, molecules are linked by pairs of C—H...O hydrogen bonds, forming inversion dimers. The dimers are linked by further C—H...O contacts, forming a three-dimensional structure

Урожайність різних сортів зернових культур озимих залежно від строків сівби в умовах Причорномор'я

The object of research is the processes of formation of productivity and quality of crops depending on the agrochemical composition of the soil.The aim of research is creation of information and methodological support for the evaluation of new varieties for different abiotic conditions and to develop innovative technologies for growing winter crops.The scientific bases of the influence of sowing periods on the formation of yield of promising winter wheat and winter barley varieties are developed.Positive response of new winter wheat varieties to different sowing periods is revealed.It is established that sowing periods should be set differentially for varieties with different periods of vernalization and different photoperiodic sensitivity.It is determined that sowing time has a significant impact on the grain yield of winter cereals studied in the experimentОбъект исследований – процессы формирования продуктивности и качества зерна зерновых культур в зависимости от разных абиотических условий.Цель исследований - создать информационное и методическое обеспечение для оценки новых сортов к разным абиотическим условиям и разработать инновационные технологии выращивания озимых культур.Розработано научные основы влияния сроков посева на формирование урожайности перспективных сортов озимой пшеницы и озимого ячменя. Выявлена позитивная реакция озимой пшеницы и озимого ячменя на разные сроки посева.Установлено, что сроки посева должны определяться дифференцированно для сортов с разными периодами яровизации и разной фотопериодичной чувствительностьюОпределено, что сроки посева имеют существенное влияние на урожайность озимых зерновых культур, которые изучались в опытахОб’єкт досліджень – процеси формування продуктивності і якості зерна зернових культур за різних абіотичних умов.Мета досліджень - створити інформаційне і методичне забезпечення для оцінки нових сортів до різних абіотичних умов та розробити інноваційні технології вирощування озимих культур.Розроблено наукові основи впливу строків сівби на формування врожайності перспективних сортів озимої пшениці та озимого ячменю. Виявлена позитивна реакція нових сортів озимої пшениці і озимого ячменя на різні строки сівби.Встановлено, що строки сівби повинні відзначатися диференційовано для сортів з різними періодами яровизації й різної фотоперіодичної чутливості.Визначено, що строки сівби мають суттєвий вплив на урожайність зерна озимих зернових культур, які вивчаються у дослід

Crystal structures of the solvent-free and ethanol disolvate forms of 4,4′-(diazenediyl)bis(2,3,5,6-tetrafluorobenzoic acid) exemplifying self-stabilized azobenzene cis-configurations

cis-4,4′-(Diazenediyl)bis(2,3,5,6-tetrafluorobenzoic acid), C14H2F8N2O4, and its ethanol disolvate, C14H2F8N2O4·2C2H5OH, represent new examples of self-stabilized cis-configured azobenzenes obtained by a common crystallization procedure at room temperature under normal laboratory lighting conditions. The target structure constitutes of two 2,3,5,6-tetrafluorobenzoic acid residues linked to each other by a cis-configured azo group and was confirmed for two isolated specimens extracted from the same sample, corresponding to a solvent-free form and an ethanol disolvate. In the solvent-free form, the molecule is characterized by rotational symmetry around a twofold rotation axis bisecting its central N=N bond while this symmetry is not present in the solvated form. The values of the inclination angles of the terminal carboxyl groups towards the corresponding benzene rings vary from 5.2 (4) to 45.7 (2)°, depending on the crystal composition. In the unsolvated form, the molecules are linked through identical hydrogen bonds with a classical R22(8) graph-set ring motif of carboxylic acids, by generating supramolecular chains running approximately parallel to [101]. The presence of ethanol in the solvated form also leads to changes in the short-contact pattern to produce both the R44(12) ring and open-chain motifs with alternating alcohol and dicarboxylic acid molecules