1,721,097 research outputs found
Molecular Modeling for Nanomaterial-Biology Interactions: Opportunities, Challenges, and Perspectives
No full textInjection of nanoparticles (NP) into the bloodstream leads to the formation of a so-called "nano-bio" interface where dynamic interactions between nanoparticle surfaces and blood components take place. A common consequence is the formation of the protein corona, that is, a network of adsorbed proteins that can strongly alter the surface properties of the nanoparticle. The protein corona and the resulting structural changes experienced by adsorbed proteins can lead to substantial deviations from the expected cellular uptake as well as biological responses such as NP aggregation and NP-induced protein fibrillation, NP interference with enzymatic activity, or the exposure of new antigenic epitopes. Achieving a detailed understanding of the nano-bio interface is still challenging due to the synergistic effects of several influencing factors like pH, ionic strength, and hydrophobic effects, to name just a few. Because of the multiscale complexity of the system, modeling approaches at a molecular level represent the ideal choice for a detailed understanding of the driving forces and, in particular, the early events at the nano-bio interface. This review aims at exploring and discussing the opportunities and perspectives offered by molecular modeling in this field through selected examples from literature
Influence des propriétés des noyaux des micelles polymériques sur l'internalisation cellulaire
No full textActuellement, encore la majorité des nouveaux principes actifs sont hydrophobes. La difficulté de solubilisation dans l'eau rend leur biodisponibilité mauvaise. De nombreux médicaments candidats sont alors éliminés lors des études pré-cliniques. Afin de résoudre ce problème, de nouvelles formes galéniques ont été développées, notamment les micelles polymériques, les liposomes, les nanoparticules ou encore les microsphères. Ces nouvelles technologies sont également un moyen de vectoriser les principes actifs, de les protéger et de contrôler la libération de la substance. Parmi ces derniers, les micelles polymériques, de structures couronne-noyau, formées par des polymères amphiphiles attirent de plus en plus l'attention des chercheurs grâce à leur stabilité, leur faible toxicité et surtout leur capacité d'encapsuler une grande quantité de principe actif hydrophobe dans le noyau micellaire
Synthesis and Characterization of Triblock Copolymeric Micelles for siRNA Delivery to NSCLC Cells
No full textSmall interfering ribonucleic acids (siRNAs) have the potential to silence genetic sequences without altering the host genome, making them a promising candidate for anti-cancer therapy. However, their large size, anionic nature, and sensitivity to degradation prevent direct use. To address this issue, numerous siRNA delivery systems, including polymeric micelles, have been investigated. This thesis reviewed different micellar polymer systems and focused on the active targeting of these compounds. The main polymeric building blocks were identified, and the safety aspect was examined.
The aim of this project was to apply computational design methods and to synthesize a tailor-made micelle for siRNA transport to minimize the risk of toxicity. The micellar model was used for predictive optimization of binding efficiency by in silico methods and applied in vitro to treat human non-small cell lung cancer cells. These cells were resected from a tumor of a patient of the University Hospitals of Geneva (HUG).
In addition, the preparation of a model antibody antigen-binding fragment that could be precisely added to the delivery system was studied. The preparation process was monitored by UPLC-HRMS.</p
Etude d'agrégation d'une protéine thérapeutique, l'interféron alpha 2b
No full textCe travail de recherche a pour objectif de mimer la formation d'agrégats lors des différentes étapes du processus de fabrication des médicaments biothérapeutiques. Différents facteurs externes tel que l'augmentation de la température et le stress mécanique, ainsi que le changement de formulation par l'ajout de l'huile de silicone ont été appliqués à la protéine IFN-α2b afin d'accélérer la formation d'agrégats. Les agrégats générés sont détectés, caractérisés et quantifiés par diffusion dynamique de la lumière, spectroscopie de fluorescence et d'absorption UV-visible, dichroïsme circulaire et par la mesure de la turbidité
Unravelling the modulation of tight junctions: Molecular mechanisms and permeation enhancement
No full textThe pharmacokinetic parameters of a therapeutic molecule are crucial. Absorption in the first instance gives the drug the opportunity to enter the body and reach the systemic circulation. Some treatments are poorly or not at all absorbed through the epithelia. They are therefore invasively administered. Facilitating and increasing the absorption of molecules would make it possible to reduce administered doses and also to change the route of administration of certain treatments for non-invasive administration, such as a nasal spray or eye drops. Tight junctions (TJs) are a set of proteins responsible for holding cells together and regulating the permeability of exogenous nutrients and compounds across the cell layer. Controlled modulation of TJs could increase the absorption of drugs across the mucosa. The enzyme protein kinase C zeta (PKC ζ) has been shown to be one of the modulators responsible for the expression of TJs proteins such as occludin and Zonula occludens (ZO). This enzyme is also involved in the activation of these proteins to close TJs. Thus, inhibition of PKC ζ activity would prevent closure of TJs and transiently increase the permeability of molecules across the epithelium. In the structure of PKC ζ, a part called pseudosubstrate (PS) has been identified as the autoinhibitory segment of the enzyme's activity. The creation of a synthetic peptide with the same sequence as this segment could inhibit PKC ζ activity using the enzyme's natural mechanism. Our L-R5 pentapeptide with a myristoylated tail was used, optimised and tested throughout this thesis. The objectives of this PhD thesis were (1) to attest to the efficacy and non-toxicity of L-R5 in opening TJs, (2) to determine the exact mechanism of inhibition of PKC ζ activity by L-R5, (3) to explore the possibilities of optimisation in the sequence and structure of L-R5 and (4) to produce a L-R5 coupled insulin formulation for nasal administration
Thermochimiothérapie : étude in vitro des interactions entre principes actifs anticancéreux et chaleur
No full textLe traitement du cancer de la prostate, et en particulier les métastases osseuses, reste un défi majeur de l'oncologie. Ce travail s'inscrit dans le contexte d'un projet développant une approche locale, combinant chimiothérapie et hyperthermie dans un système médical injectable. L'hyperthermie, un adjuvant reconnu dans le traitement du cancer, potentialise l'effet de certains anticancéreux et une synergie peut être attendue améliorant ainsi l'efficacité des traitements chimiothérapeutiques. L'objectif de ce travail est d'étudier les effets de la combinaison hyperthermie-chimiothérapie in vitro sur la lignée cellulaire d'adénocarcinome de prostate humaine PC3
Extraction de prophages du génome de Pseudomonas aeruginosa par la méthode CRISPR/Cas9
No full textFace à l'émergence de bactéries multirésistantes aux antibiotiques, la phagothérapie suscite beaucoup d'intérêts afin de contrer ce problème de santé publique (1,2). Elle utilise des virus appelés bactériophages ou « phages » afin d'éliminer les bactéries infectieuses. Cette méthode a déjà pu faire ses preuves, il y a environ 100 ans, contre des maladies infectieuses comme le choléra ou la peste (3–5). Les phages se distinguent en deux groupes : les phages lytiques (utilisés en phagothérapie) et les phages tempérés (2,4,6,7). Les phages lytiques tuent immédiatement les bactéries, tandis que les phages tempérés s'intègrent à leur génome, devenant alors des prophages
Développement de micelles polymériques pour le ciblage du cancer : Development of polymeric micelles for cancer targeting
No full textCancer is one of the most dreaded diseases. It is a major threat to human life. All over the world 12 million people were diagnosed with cancer, and 7.6 million people died because of cancer diseases in 20081. Odiously medical treatment and drugs currently on the market are not efficient enough. More over potent drug are not only internalized by cancer cell but also by healthy cells and tissues with consequent cellular toxicity and severe side effects2. For these reasons cancer treatment is still one of the most problematic treatments. Although a lot of progress has been made on this topic, there is still not an optimal therapy available. A non-invasive approach of drug administration is desirable, and is widely studied in combination with nanotechnologies. There are many various forms of “nanoapproaches”, such as drug formulation with liposomes, nanospheres, nanocapsules and micelles. Micelle formulations are of high interest3
Toll-like receptor agonist decorated chitosan nanoparticles for pulmonary DNA vaccination
No full textCe travail de thèse vise à l´évaluation de nouvelles nanoparticules (NP) vectorisant un antigène sous forme d'acide nucléique, fonctionnalisées par de puissants adjuvants pour une vaccination par voie respiratoire. La vaccination par ADN est une nouvelle approche vaccinale pour induire une réponse immunitaire spécifique contre un agent pathogène. Suite à son administration, un vaccin à ADN permet la synthèse in vivo de l´antigène, puis sa présentation sous forme de peptides antigéniques par les molécules du complexe majeur d´histocompatibilité (CMH) de classe I. Par conséquent, les lymphocytes T CD8+ sont stimulés, et déclenchent une réponse cytotoxique dirigée contre l´antigène. Malgré des résultats pré-cliniques prometteurs de vaccination par ADN, les essais réalisés chez le primate ou chez l'Homme n´ont pas permis l'induction d'une réponse immunitaire protectrice. A cause de cela, plusieurs stratégies ont été proposées, comme le changement de la voie d'administration, la complexation de l'ADN avec un polymère sous forme (nano)particulaire ou l´ajout d´un adjuvant
Development of novel PEGylation approaches based on non-covalent interactions
No full textBiopharmaceuticals hold important value for the treatment of severe diseases. However, stability concerns remain one of the main obstacles for their successful market authorization. Generally, physical instabilities (in particular aggregation), in vivo immunogenicity, and short circulation half-lifes due to enzymatic degradation and fast renal elimination pose major challenges. After PEGylation, the covalent conjugation of poly(ethylene glycol) to biopharmaceuticals, decreased enzymatic degradation, prolonged plasma half-lifes, reduced in vivo immunogenicity, and improved formulation stability have been reported. However, several challenges remain for covalent PEGylation: i) the chemical processing and subsequent purification needed to attach the PEG may represent further stress on the protein, resulting in increased aggregation and possible loss of activity, ii) heterogeneous products are obtained requiring separation and characterization, and iii) an observed reduced in vivo bioactivity resulting from decreased interactions of the drug with its receptor due to steric shielding by the PEG. As described in this thesis, we addressed the need for alternative PEGylation approaches by development of novel techniques based on non-covalent interactions
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