Développement de formes solides non conventionnelles pour la chimiothérapie orale

Cette thèse porte sur la transformation de l'état solide d'une molécule active pharmaceutique anti-cancéreuse, Erlotinib (ERL) en deux différentes formes sursaturées (dispersions solides amorphes et co-cristaux). Pour définir les 2 formes solides, les dispersions solides sont basées sur une technologie de formulation dans laquelle le principe actif est dispersé dans un support amorphe. Elle facilite la dissolution des médicaments peu solubles dans l'eau principalement en présentant le médicament sous une forme amorphe. Les co-cristaux, quant à eux, sont généralement composés dans un rapport stœchiométrique d'un ingrédient actif et d'une molécule non toxique appelée co-formeur. Ces formes visent à limiter les effets secondaires en améliorant la biodisponibilité de la molécule lors d'une chimiothérapie orale. Les paramètres de l'étude ont été les polymères pour les dispersions solides amorphes et les co-formers pour les co-cristaux et les procédés de synthèse (séchage par atomisation et extrusion à chaud pour les dispersions solides amorphes et cristallisation en solution pour les co-cristaux). Après un travail de synthèse et caractérisation des deux formes solides d'ERL, elles ont été comparées en termes de solubilité en milieu aqueux et dissolution in vitro. Les dispersions solides amorphes ont montré un meilleur effet sur la solubilité de l'ERL à un pH de 6,8 et l'inhibition de la cristallisation de l'ERL pendant le transfert simulé gastrique-intestinal.This thesis focuses on the solid state transformation of an anti-cancer pharmaceutical active molecule, Erlotinib (ERL), into two different supersaturated forms (amorphous solid dispersions and co-crystals). To define the 2 solid forms, solid dispersions are based on a formulation technology in which the active ingredient is dispersed in an amorphous carrier. It facilitates the dissolution of poorly water-soluble drugs mainly by presenting the drug in an amorphous form. Co-crystals, on the other hand, are generally composed in a stoichiometric ratio of an active ingredient and a non-toxic molecule called a co-former. These forms aim to limit side effects by improving the bioavailability of the molecule during oral chemotherapy. The parameters of the study were the polymers for the amorphous solid dispersions and the co-formers for the co-crystals and the synthesis processes (spray drying and hot melt extrusion for the amorphous solid dispersions and solution crystallization for the co-crystals). After synthesis and characterization of the two solid forms of ERL, they were compared in terms of solubility in aqueous medium and in vitro dissolution. The amorphous solid dispersions showed a better effect on ERL solubility at pH 6.8 and inhibition of ERL crystallisation during simulated gastric-intestinal transfer

Mechanical Strain Measurements in High-Field Low-Temperature Superconducting Magnets

Optical fiber sensors based on Fiber Bragg Grating (FBG) technology are used to monitor the mechanical behavior of the magnet's coils from its assembly at room temperature to its powering at cryogenic temperatures. The development of this instrumentation required several years of research and development effort to validate the precision and accuracy of FBGs based measurements in cryogenic conditions. FBGs are bonded on the coils in different locations along with the longitudinal and azimuthal directions that allow studying the average stress levels. The stainless-steel shells of the magnets and each extremity of the four rods are equipped with resistive strain gauges (RSG). This paper provides a description of the instrumentation used to monitor the strain profile of superconducting magnets. Strain measurements during magnet assembly, cool-down, and powering are presented to confirm the agreement between electrical and optical sensors

Characterization and PCR-Based Replicon Typing of Resistance Plasmids in Acinetobacter baumannii▿

Acinetobacter baumannii is an opportunistic pathogen, especially in intensive care units, and multidrug-resistant isolates have increasingly been reported during the last decade. Despite recent progress in knowledge of antibiotic resistance mechanisms in A. baumannii, little is known about the genetic factors driving isolates toward multidrug resistance. In the present study, the A. baumannii plasmids were investigated through the analysis and classification of plasmid replication systems and the identification of A. baumannii-specific mobilization and addiction systems. Twenty-two replicons were identified by in silico analysis, and five other replicons were identified and cloned from previously uncharacterized A. baumannii resistance plasmids carrying the OXA-58 carbapenem-hydrolyzing oxacillinase. Replicons were classified into homology groups on the basis of their nucleotide homology. A novel PCR-based replicon typing scheme (the A. baumannii PCR-based replicon typing [AB-PBRT] method) was devised to categorize the A. baumannii plasmids into homogeneous groups on the basis of the nucleotide homology of their respective replicase genes. The AB-PBRT technique was applied to a collection of multidrug-resistant A. baumannii clinical isolates carrying the blaOXA-58 or blaOXA-23 carbapenemase gene. A putative complete conjugative apparatus was identified on one plasmid whose self-conjugative ability was demonstrated in vitro. We showed that this conjugative plasmid type was widely diffused in our collection, likely representing the most important vehicle promoting the horizontal transmission of A. baumannii resistance plasmids

Analytical tolerancing of segmented telescope co-phasing for exo-Earth high-contrast imaging

International audienceThis paper introduces an analytical method to calculate segment-level wavefront error (WFE) tolerances to enable the detection of faint extra-solar planets using segmented-aperture telescopes in space. This study provides a full treatment of the case of spatially uncorrelated segment phasing errors for segmented telescope coronagraphy, which has so far only been approached using ad-hoc Monte Carlo (MC) simulations. Instead of describing the wavefront tolerance globally for all segments, our method produces spatially dependent requirement maps. We relate the statistical mean contrast in the coronagraph dark hole to the standard deviation of the WFE of each individual segment on the primary mirror. This statistical framework for segment-level tolerancing extends the Pair-based Analytical model for Segmented Telescope Imaging from Space (PASTIS), which is based uniquely on a matrix multiplication for the optical propagation. We confirm our analytical results with MC simulations of end-to-end optical propagations through a coronagraph. Comparing our results for the Apodized Pupil Lyot Coronagraph designs for the Large Ultraviolet Optical Infrared telescope to previous studies, we show general agreement but we provide a relaxation of the requirements for a significant subset of segments in the pupil. These requirement maps are unique to any given telescope geometry and coronagraph design. The spatially uncorrelated segment tolerances we calculate are a key element of a complete error budget that will also need to include allocations for correlated segment contributions. We discuss how the PASTIS formalism can be extended to the spatially correlated case by deriving the statistical mean contrast and its variance for a non-diagonal aberration covariance matrix. The PASTIS tolerancing framework therefore brings a new capability that is necessary for the global tolerancing of future segmented space observatories

Isolation and Characterization of Fasciculin Ii: From Dendroaspis Angusticeps Snake Venom and from Chemical Synthesis

WOS:00043691790003

Isolation of an Anti-Tumour Disintegrin: Dabmaurin-1, a Peptide Lebein-1-Like, from Daboia mauritanica Venom.

International audienceIn the soft treatment of cancer tumours, consequent downregulation of the malignant tissue angiogenesis constitutes an efficient way to stifle tumour development and metastasis spreading. As angiogenesis requires integrin-promoting endothelial cell adhesion, migration, and vessel tube formation, integrins represent potential targets of new therapeutic anti-angiogenic agents. Our work is a contribution to the research of such therapeutic disintegrins in animal venoms. We report isolation of one peptide, named Dabmaurin-1, from the hemotoxic venom of snake Daboia mauritanica, and we evaluate its potential anti-tumour activity through in vitro inhibition of the human vascular endothelial cell HMECs functions involved in tumour angiogenesis. Dabmaurin-1 altered, in a dose-dependent manner, without any significant cytotoxicity, HMEC proliferation, adhesion, and their mesenchymal migration onto various extracellular matrix proteins, as well as formation of capillary-tube mimics on MatrigelTM. Via experiments involving HMEC or specific cancers cells integrins, we demonstrated that the above Dabmaurin-1 effects are possibly due to some anti-integrin properties. Dabmaurin-1 was demonstrated to recognize a broad panel of prooncogenic integrins (αvβ6, αvβ3 or αvβ5) and/or particularly involved in control of angiogenesis α5β1, α6β4, αvβ3 or αvβ5). Furthermore, mass spectrometry and partial N-terminal sequencing of this peptide revealed, it is close to Lebein-1, a known anti-β1 disintegrin from Macrovipera lebetina venom. Therefore, our results show that if Dabmaurin-1 exhibits in vitro apparent anti-angiogenic effects at concentrations lower than 30 nM, it is likely because it acts as an anti-tumour disintegrin

Predicting contrast sensitivity to segmented aperture misalignment modes for the HiCAT testbed

International audienceThis paper presents the setup for empirical validations of the Pair-based Analytical model for Segmented Telescope Imaging from Space (PASTIS) tolerancing model for segmented coronagraphy. We show the hardware configuration of the High-contrast imager for Complex Aperture Telescopes (HiCAT) testbed on which these experiments will be conducted at an intermediate contrast regime between 10-6 and 10-8. We describe the optical performance of the testbed with a classical Lyot coronagraph and describe the recent hardware upgrade to a segmented mode, using an IrisAO segmented deformable mirror. Implementing experiments on HiCAT is made easy through its top-level control infrastructure that uses the same code base to run on the real testbed, or to invoke the optical simulator. The experiments presented in this paper are run on the HiCAT testbed emulator, which makes them ready to be performed on actual hardware. We show results of three experiments with results from the emulator, with the goal to demonstrate PASTIS on hardware next. We measure the testbed PASTIS matrix, and validate the PASTIS analytical propagation model by comparing its contrast predictions to simulator results. We perform the tolerancing analysis on the optical eigenmodes (PASTIS modes) and on independent segments, then validate these results in respective experiments. This work prepares and enables the experimental validation of the analytical segment-based tolerancing model for segmented aperture coronagraphy with the specific application to the HiCAT testbed

Gd³⁺-Functionalized Lithium Niobate Nanoparticles for Dual Multiphoton and Magnetic Resonance Bioimaging

Harmonic nanoparticles (HNPs) have emerged as appealing exogenous probes for optical bioimaging due to their distinctive features such as long-term photostability and spectral flexibility, allowing multiphoton excitation in the classical (NIR-I) and extended near-infrared spectral windows (NIR-II and -III). However, like all other optical labels, HNPs are not suitable for whole-body imaging applications. In this work, we developed a bimodal nonlinear optical/magnetic resonance imaging (MRI) contrast agent through the covalent conjugation of Gd(III) chelates to coated lithium niobate HNPs. We show that the resulting nanoconjugates exert strong contrast both in T1-weighted MRI of agarose gel-based phantoms and in cancer cells by harmonic generation upon excitation in the NIR region. Their capabilities for dual T1/T2 MRI were also emphasized by the quantitative mapping of the phantom in both modes. The functionalization protocol ensured high stability of the Gd-functionalized HNPs in a physiological environment and provided a high r1 relaxivity value per NP (5.20 x 105 mM-1 s-1) while preserving their efficient nonlinear optical respons

Gd3+-Functionalized Lithium Niobate Nanoparticles for Dual Multiphoton and Magnetic Resonance Bioimaging

Harmonic nanoparticles (HNPs) have emerged as appealing exogenous probes for optical bioimaging due to their distinctive features such as long-term photostability and spectral flexibility, allowing multiphoton excitation in the classical (NIR-I) and extended near-infrared spectral windows (NIR-II and -III). However, like all other optical labels, HNPs are not suitable for whole-body imaging applications. In this work, we developed a bimodal nonlinear optical/magnetic resonance imaging (MRI) contrast agent through the covalent conjugation of Gd(III) chelates to coated lithium niobate HNPs. We show that the resulting nanoconjugates exert strong contrast both in T1-weighted MRI of agarose gel-based phantoms and in cancer cells by harmonic generation upon excitation in the NIR region. Their capabilities for dual T1/T2 MRI were also emphasized by the quantitative mapping of the phantom in both modes. The functionalization protocol ensured high stability of the Gd-functionalized HNPs in a physiological environment and provided a high r1 relaxivity value per NP (5.20 × 105 mM–1 s–1) while preserving their efficient nonlinear optical response.GCCSCI-SB-S