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The present invention concerns amphiphilic copolymers that may be photo- or redox-cleavable and that may assemble into polymersomes. It also concerns their process of preparation and their use as drug carriers.; La présente invention concerne des copolymères amphiphiles qui peuvent être photo-clivables ou clivables par oxydoréduction et qui peuvent s'assembler en polymersomes. L'invention concerne également leur procédé de préparation et leur utilisation en tant que supports de médicament.

International audience; In medicine, medical imaging has a leading place in the diagnosis setting. This is why some researches are continually carried out to improve the available techniques. One of the most used techniques to obtain anatomical information is magnetic resonance imaging (MRI). The commercially available contrast agents are based on gadolinium complexes. Recently, it has been shown that gadolinium can lead, mainly for patients with renal disfunctions, to a pathology named NSF (nephrogenic systemic fibrosis). It is thus interesting to develop efficient contrast agents based on another paramagnetic ion such as manganese. The macrocycle used in this work is a pyclen derivative which is functionalized to respect protection anddeprotection steps. Their efficacy as contrast agents for MRI was evaluated by relaxometry and 17O NMR and even if the results are encouraging, the manganese ion is, as expected, less effective than the gadolinium ion. So, it could be interesting to encapsulate the Mn-complexes in nanostructure like polymersomes which allow a fast exchange of the water molecules through the pores. The complexes could thus be encapsulated inside the polymersomes or in the membrane in order to improve the relaxivity through an increase of the rotational correlation time.

International audience; Intimate mixing of phospholipids and amphiphilic copolymers within same membrane of a giant vesicle requires particulate attention on both the molecular design and on the self-assembly process for synergetic benefits from both components.

With the current increase of asymmetric conflicts, a bioterrorist attack against the French armed forces or on the national territory is unfortunately no longer excluded. FASTGENE technology enables the sensitive, specific and inexpensive detection of the presence of pathogens in a sample in less than 8 minutes. This dual technology can be applied to many other applications outside the field of defense and security, Avec l'accroissement actuel des conflits asymétriques, une attaque bioterroriste à l'encontre des forces armées françaises ou sur le territoire national n'est malheureusement plus à exclure. Avec le soutien de la DGA, nous avons développé la technologie FASTGENE qui permet la détection sensible, spécifique et peu coûteuse, de la présence d'agents pathogènes dans un échantillon en moins de 8 minutes. Cette technologie duale peut s'appliquer de nombreuses autres applications en dehors du domaine de la défense et de la sécurité. Détecter et identifier rapidement les microorganismes: un besoin essentiel pour contrer les bioterroristes Le risque bioterroriste est particulièrement préoccupant puisqu'il se différencie des autres risques terroristes par des effets initialement masqués, puis amplifiés exponentiellement par le caractère contagieux d'un nombre croissant d'infections. La capacité de défense vis-à-vis de ce risque repose sur plusieurs piliers parmi lesquels la surveillance de l'environnement et la reconnaissance d'une agression jouent un rôle central. Une surveillance permanente et une reconnaissance rapide permettent en principe de limiter au maximum les conséquences d'une attaque. A la suite de l'attaque par lettres contenant des bacilles du charbon en 2001, les autorités des États-Unis ont décidé de déployer au niveau fédéral un système de surveillance de la qualité biologique de l'air, appelé Biowatch (1). Ce système est composé d'un grand nombre de capteurs d'aérosols déployés dans les 30 plus grandes agglomérations. Les aérosols ainsi collectés sont analysés périodiquement par un réseau de laboratoires. Bien que ce système unique n'ait heureusement jamais été confronté à une attaque bioterroriste, son exploitation permet de tirer plusieurs enseignements capitaux sur les caractéristiques que doivent réunir un tel système

Magnetic nanoparticles present some attractive applications in biomedicine. First, they can be prepared from a size ranging from a few nanometers up to hundreds of nanometers, which places the particles at dimensions that are smaller than or comparable to those of cells (10–100 μm), virus (20–450 nm), proteins (5–50 nm) and genes (2 nm wide and 10–100 nm long). As a consequence they can “get close” to these biological entities. Furthermore, when coated with appropriate molecules magnetic nanoparticles can interact or bind to biological entities, which provides a mean of actuating on these entities by noncontact magnetic forces. This ‘action at a distance’, combined with the intrinsic penetrability of magnetic fields into biological tissues, possibilities a number of biomedical applications of magnetic nanoparticles.In this seminar, a revision of the state of the art in the fields of synthesis, properties and biomedical applications of magnetic nanoparticles is presented. This seminar is organized as it follows:1. Chemistry of iron oxides and oxo-hydroxides: Diversity of methods to prepare colloidal nanoparticles, either in non aqueous solvents: hydrothermal synthesis, polyol synthesis, thermal decomposition… or in water: co-precipitation of iron salts2. Magnetic behavior: ferro- /ferri- /antiferro- /superpara– magnetism, magnetophoresis (magnetic guiding)3. Optical properties: UV-vis absorption, circular dichroism (Faraday rotation), magnetic birefringence4. Relaxivity properties (T1/T2 of H spins): Contrast agents in MRI5. Magnetic relaxations in radiofrequency (kHz-MHz) fields: Magnetic hyperthermia and RF-induced drug release

International audience; Reflets de la physique constitue avec le site web l outil de communication privilégié de la SFP auprès de ses membres

International audience; Phase separation in hybrid polymer/lipid giant unillamelar vesicles (GHUVs) has been described over the last few years. However there is still a lack of understanding in physical and molecular factors governing the phase separation in such systems. Among these parameters it has been suggested that in analogy to multicomponent lipid vesicles that hydrophobic mismatchs as well as lipid fludity play a role.In this work, we aim to map a global picture of phase separation and domain formation in membrane of GHUVs by using various copolymers based on poly(dimethylsiloxane) (PDMS) and poly(ethylene glycol) (PEO) with different architectures (grafted, triblock) and molar masses, combined with lipid at fluid (POPC) or gel state (DPPC) at room temperature. From confocal imaging and fluorescence lifetime imaging microscopy technique (FLIM), the phase separation into either micro- or nano- domains within GHVs were studied. In particular, our systematic studies demonstrate that in addition to lipid/polymer fraction or lipid physical state, important factors such as line tension at lipid polymer/lipid boundaries can be finely modulated by the molar mass and architecture of the copolymer and lead to the formation of stable lipid domains with different sizes and morphologies in such GHUVs.

International audience; Hybrid vesicles resulting from the combined self-assembly of both amphiphilic copolymers and lipids have attracted particular interest from chemists and (bio)physicists over the last five years. Such assemblies may be viewed as an advanced vesicular structure compared to their liposome and polymersome forerunners as the best characteristics from the two different systems can be integrated in a new, single vesicle. To afford such a design, the different parameters controlling both self-assembly and membrane structure must be tuned. This highlight aims to present a comprehensive overview of the fundamental aspects related to these structures, and discuss emerging developments and future applications in this field of research.

The ability of certain lipids to self-assemble in water as bilayers is crucial for the properties of the outer membrane of biological cells and many of their internal structures as well (Golgi apparatus, endosomes, lysosomes, ...). Usually we call a vesicle such a bilayer membrane forming a closed shape with both an inner and an outer aqueous compartments separated by a hydrophobic barrier with a nearly zero permeability to hydrophilic solutes. This vesicular morphology well-known for liposomes prepared from either natural or artificial lipids was also obtained recently for polymersomes, which membrane is made of block copolymers[1]. It is worth noticing that unlike other manmade capsules or natural shells, the membrane of liposomes and polymerosomes is a 2-dimensional fluid. The result is a large flexibility of the shape and a mobility of the molecules within the membrane. The encapsulation of the magnetic nanoparticles of ferrofluids into vesicles was motivated by the idea of controlling their shape by an external magnetic field. Giant magneto-liposomes were first obtained by pre-hydrating a synthetic phospholipid (DOPC) with an aqueous “citrated” ferrofluid at pH7 and subsequent swelling of the bilayers by water[2]. Their diameters ranging from 5 to 20 um, it was possible to use optical microscopy to study their elongation in a homogeneous magnetic field and deduce the bending modulus of the DOPC bilayers Kb=20kBT from those measurements. In following experimental[3] and theoretical[4] works, it was shown that a magnetic field could produce either a prolate or an oblate ellipsoidal deformation of the magnetic liposomes depending on another control parameter important for ionic ferrofluids: the citrate salt concentration. When the concentration of those small ions is small indeed, the spontaneous curvature due to the difference between the Debye lengths on each side of the bilayer becomes sensitive to the presence of the nanoparticles inside and their absence outside. It was shown that the bending energy dominates over the magnetic energy in that case, and thus that an oblate flattening of the vesicle near the magnetic poles is preferred to the prolate elongation observed at high salinity. The citrate salt concentration in the outer medium of the giant magneto-liposomes was also used as an osmotic agent to measure the permeability of water through DOPC bilayers[5]. In other experiments, tubular giant magneto-liposomes were favoured by shearing the bilayers during their swelling by water[6]. The true morphology was rather like dumbbells because the cylindrical portions of membranes were connecting two quasi-spherical vesicles with a high concentration of ferrofluid inside. The deformation of such connected vesicles by an applied magnetic field is much larger than for isolated vesicles because the connected tubules act as reservoirs of lipids adding to the surface area of the spherical parts. Above a threshold field intensity, a pearling instability of the tubules is induced by the increase of the surface tension. Current researches on giant magneto-liposomes deal with their use as directly observable objects (under an optical microscope) to visualize the intermediate steps during the solubilization of lipid bilayers by n-octylglucoside (OG), a non ionic surfactant commonly used in pharmacology. By using the deformation experiment with a magnetic field to probe the membrane elasticity, it was shown that at bulk concentrations below the CMC, the penetration of surfactants in the bilayers causes a 10% relative increase of their surface area and a lowering of Kb down to 5 kBT. [7] At a lower (sub-micronic) scale, large unilamellar vesicles (LUV) were successfully prepared with a high encapsulation yield of magnetic nanoparticles[8] (Fig. 1), which could be used as new magnetic vectors In spite of the lack of experimental example, the deformation by a field of a vesicle with a fluid and magnetic membrane was addressed theoretically[9]. Having managed to confine magnetic nanoparticles in the membrane of polymersomes (Fig. 2) much thicker than lipid bilayers[10], we are now studying their response to a field.for drug targeting or contrast agents in MRI.

Giant vesicles are artificial objects used to mimic the lipid envelope of biological cells, or plasma membrane, delimiting the cell interior from the outer medium. Among all the systems modeling biological membranes (monomolecular layers at the air/water interface, bilayers supported on a solid substrate, black lipid membranes, etc.…), giant vesicles are the softest and the easiest to change their shapes. Their membrane is a thin fluid sheet with indeed almost no surface tension. Nevertheless, it can be stretched by an external action. The value of the so created mechanical tension lies far below the usual interfacial tensions of liquids. However, with giant vesicles, the necessity to relax this low tension is a sufficient factor to cause major reorganizations of lipids. This work highlights two types of transformation: i) transient rupture of the membrane, and the leakage of the inner fluid through a giant macroscopic pore; ii) fusion of neighboring membranes, via the steps of hemifusion and then of a fusion pore. Experimental observations have been obtained mainly by fluorescence microscopy. A simple hydrodynamic theory describes the viscous dissipation inside the membrane and in the surrounding solvent. Besides, a novel imaging technique developed recently, namely the second harmonic generation (SHG) microscopy provides complementary information about the distance profile of adhering membranes. Finally, giant vesicles decorated with proteins enable to get a little closer to the reality of cell adhesion.Chapter I presents the general characteristics of vesicles, and the manipulations enabling to put them under tension. The experimental protocols are described in chapter II, to prepare on the one hand suspensions of giant vesicles in various mediums, on the other hand adhesive coatings on glass. Chapter III details the methods of optical microscopy, in order to observe the lipid membranes with the best contrast. After a brief state of the art about the break-down of lipid bilayers, chapter IV describes the complete dynamics of transient pores, both theoretically and experimentally. In particular, we shall see how the increased viscosity of the medium leads to longer lifetimes together with larger sizes. Chapter V just reveals descriptively the foams of giant vesicles. Depending on the type of interaction, vesicles either remain tense as soap bubbles, or they relax their tension by mixing part of their membranes., Les vésicules géantes sont des objets artificiels utilisés pour mimer l’enveloppe lipidique des cellules biologiques, la membrane plasmique, qui sépare l’intérieur de la cellule de son milieu extérieur. Parmi tous les systèmes censés modéliser les membranes biologiques (couches monomoléculaires à l’interface eau/air, bicouches supportées sur un substrat solide, films noirs lipidiques, etc...) les vésicules géantes sont les plus molles et les plus déformables. En effet, leur membrane est une mince couche fluide dont la tension de surface est pratiquement nulle. Néanmoins, elle peut être tendue progressivement par une action extérieure. La tension mécanique qui apparaît alors reste très en deçà des tensions interfaciales usuelles des liquides. Mais, sur des vésicules géantes, la relaxation de cette tension suffit pour provoquer des réorganisations importantes des lipides. Ce travail met en lumière deux types de transformation : i) la rupture transitoire de la membrane, et la fuite du liquide interne à travers un pore macroscopique géant ; ii) la fusion de deux membranes adjacentes, qui passe par les étapes intermédiaires d’hémifusion puis d’un pore de fusion. Les observations expérimentales ont été réalisées principalement en microscopie de fluorescence. Un modèle hydrodynamique simple étudie la dissipation visqueuse à l’intérieur de la membrane et dans le solvant alentour. En parallèle, une nouvelle imagerie mise au point récemment, la microscopie par génération de second harmonique (SHG), apporte des informations complémentaires sur le profil de distance des membranes adhérentes. Enfin, des vésicules géantes décorées par des protéines permettent de s’approcher un peu plus de la réalité de l’adhésion cellulaire.Le chapitre I présente les caractéristiques générales des vésicules, ainsi que les manipulations permettant de les mettre sous tension. Les protocoles expérimentaux sont décrits au chapitre II, pour préparer d’une part des suspensions de vésicules géantes dans différents milieux, d’autre part des traitements de surfaces adhésifs sur le verre. Les méthodes de microscopie optique, nécessaires pour observer les membranes lipidiques avec un contraste optimal, sont détaillées au chapitre III. La suite aborde les deux voies adoptées par les vésicules géantes pour relaxer une tension de surface. Après un bref état de l’art sur les ruptures de bicouches lipidiques, le chapitre IV décrit, sur le plan théorique puis expérimental, la dynamique complète des pores transitoires. Nous verrons en particulier comment la viscosité accrue du milieu augmente à la fois leur durée de vie et leur taille. Le chapitre V ne fait qu’aborder, d’une manière surtout descriptive, les mousses de vésicules géantes. Suivant leur type d’interaction, soit les vésicules restent tendues comme des bulles de savon, soit elles relaxent leur tension, en mélangeant partiellement leurs membranes.

International audience

In this poster we show two types of nanocomposite materials consisting of nanoparticles embedded in polymer matrices. On the one hand, a matrix with a high degree of organization is investigated for visible light optics and hyper-frequencies applications (reflectors, guides, antennae). On the other hand, a gel matrix with an isotropic loading of nanoparticles can exhibit a swelling transition triggered by an external field (electric or magnetic) or by temperature. The first system combines the self-assembly of a symmetrical diblock copolymer matrix poly(n-butylmethacrylate)-b–poly(styrene) (PBMA-b-PS) and the orientation properties under magnetic field of Γ-Fe2O3 nanoparticles. To confine the nanoparticles within the layers of PBMA-b-PS (Fig.1a), those were coated by a polymeric shell grown by surface initiation polymerization of PS ("grafting from"). Thin films obtained by spin-coating and annealing above the glass temperature Tg were doped with nanoparticles. The lamellar order was investigated by neutron reflectivity experiments (Fig.1b) which enable to fit the density profile of the films and to localize precisely the nanoparticles within the first PS blocs. The second system consists of the same iron oxide nanoparticles, which are confined this time within spherical clusters of PTEA-PAM (Fig.2a., cf. Pr. Perzynski), dispersed into a thermosensitive hydrogel of poly(N-isopropylacrylamide) PNIPAM. The deswelling of the matrix above the transition temperature causes the decrease of the average distance between those clusters, as shown by small angle neutron scattering experiment (Fig.2b).

Conférence orale présentée par Bruno Frka-Petesic; International audience; Mixing in aqueous solutions polyelectrolyte-neutral block copolymers with oppositely charged species, spontaneously forms stable core-shell complexes, which are electrostatically driven. We report here on the structural and orientational properties of such mixed magnetic nanoclusters made of magnetic iron oxide nanoparticles (MNP) and polyelectrolyte-neutral block copolymers. Small Angle Neutron Scattering and Transmission Electron Microscopy experiments allows to probe the innercore nanoparticle organization, leading to an average inter-particle distance and confirming the hierarchical internal structure of the clusters. Thanks to the MNP optical anisotropy, we also probe the under-magnetic field orientational properties of the core-shell clusters and their dynamical rotational relaxation.

Nanocomposite materials which associate inorganic nanoparticles and polymers with a high degree of organization are highly interesting for their applications in visible light optics (reflectors and guides) and hyper-frequencies (antennae and switches). We focus our study on a complex system combining the self-organization of a symmetrical poly(n-butylmethacrylate)-b– poly(styrene) diblock copolymer (PBMAb- PS) and the orientation properties under magnetic field of inorganic magnetic nanoparticles made of gamma-Fe2O3 iron oxide. To confine those magnetic nanoparticles within the layers of diblock copolymer and thus obtain a lamellar order, it is necessary to coat these nanoparticles with a polymer of the same nature than one bloc of the copolymer. Such a polymeric shell can be grown by initiating polymerization of PS chains at the surface of the nanoparticles ("grafting from") or by adsorbing endfunctionnalized PS chains ("grafting on"). By spin-coating a solution of PBMA-b-PS with or without PS coated nanoparticles in a volatile solvent on a flat silicon wafer and annealing above the glass temperature, we obtain the ordering of the thin film into layers of PBMA alternating with layers of PS doped with nanoparticles. This lamellar order is detected by AFM observation showing characteristic defects such as "islands" and "holes" and by measurements of the lamellar period by Neutron Reflectivity experiments.

Poster présenté par Vincent Dupuis

Nanocomposite materials which associate inorganic nanoparticles and polymers with a high degree of organization are highly interesting for their applications in visible light optics (reflectors and guides) and hyper-frequencies (antennae and switches). We focus our study on a complex system combining self-organization of a diblock copolymer A-B and orientation properties under magnetic field of inorganic magnetic nanoparticles. We present here an experimental protocol for the synthesis by Atom Transfer Radical Polymerization (ATRP) of the symmetrical poly(n-butylmethacrylate)-b–poly(styrene) diblock copolymer (PBMA-b-PS) with high molar masses (about 100 000 g/mol). After spin-coating on a flat substrate (float glass, silicone or alumina) from a solution in a volatile solvent and annealing above the glass temperature, a thin film of such well-defined symmetrical diblocks are expected to self-organize into a lamellar (smectic type) order. The second component of the system consists in nanoparticles made of either superparamagnetic maghemite oxide Γ-Fe2O3 (soft magnets) or ferrimagnetic cobalt ferrite CoO.Fe2O3 (strong magnets). We are working on the proper dispersion of these nanoparticles within the PS blocks in order to obtain “sandwiches” made of magnetic thin layers alternating with the lamellae of the copolymer matrix. Optical Reflection Interference Contrast Microscopy (RICM) is convenient and fast to measure the thickness of the films (from a number of fringes) directly on their substrate and to detect characteristic defects of the long-range organization of the films (like holes). High resolution microscopies such as AFM and TEM will enable to measure the lamellar period but require to prepare thin films cross-sections.

Présentation orale, présentée par E. Dubois

Meyer, oral

International audience; In Ref. 1, Eq. (2) should read as, (2)Eq. (3) should read as, (3)and the right-hand side of Eq. (4) should bemultiplied by 2*2^0.5.Finally, our discussion on the N.A. dependenceof PSHG is somewhat erroneous. In fact, PSHG isroughly independent of N.A. for low N.A.’s.

International audience; This chapter contains sections titled:IntroductionLiposome PreparationObservationsAnalysis of Deformations Under a Magnetic FieldInterpretation

Ein Aspekt dieser Beschreibung bezieht sich auf eine Vorrichtung (100) zur Bestimmung charakteristischer Parameter der Abmessungen von in einer Flüssigkeit suspendierten Nanopartikeln.Die Vorrichtung (100) umfasst eine Lichtemissionseinrichtung (101), die so konfiguriert ist, dass sie einen einfallenden Strahl (Bi) emittiert, der entlang einer Polarisationsachse (P1) linear polarisiert ist; eine Erfassungseinheit (102), die einen Messarm (120) umfasst, der um eine Drehachse (∆) drehbar ist, wobei die Erfassungseinheit einen ersten und einen zweiten Erfassungskanal (151, 161) umfasst, die durch ein Polarisationstrennungselement (125) getrennt sind, das an dem Messarm angeordnet ist; einen festen Probenträger (103), der zur Aufnahme eines zylindersymmetrischen Behälters (10) der Probe konfiguriert ist, wobei eine Symmetrieachse des Behälters mit der Drehachse des Messarms zusammenfällt; eine Steuereinheit (104). Das Polarisationsteilerelement (125) des Messarms ist so konfiguriert, dass es gleichzeitig auf jedem der ersten und zweiten Detektionskanäle jeweils eine erste und eine zweite polarisierte Komponente (BS1, BS2) des von der Probe gestreuten Strahls (BS) sendet, wobei die Polarisationsachsen der ersten und zweiten polarisierten Komponenten senkrecht sind.Die Steuereinheit (104) ist so konfiguriert, dass sie aus den Signalen, die den auf jedem der Detektionskanäle detektierten polarisierten Komponenten entsprechen, als Funktion der Zeit mindestens zwei Parameter bestimmt, die für die Abmessungen der Nanopartikel charakteristisch sind., According to one aspect, the subject of the present description is a device (100) for determining characteristic parameters of the dimensions of nanoparticles in suspension in a liquid. The device (100) comprises light-emitting means (101) configured to emit an incident light beam (Bi) that is linearly polarized along a polarization axis (P1); a detecting unit (102) comprising a measurement arm (120) that is rotatable with respect to an axis of rotation (∆), said detecting unit comprising first and second detection channels (151, 161) that are separated by a polarization-splitting element (125) arranged in said measurement arm; a fixed sample holder (103), configured to receive a container (10) of cylindrical symmetry of said sample, an axis of symmetry of the container being coincident with the axis of rotation of the measurement arm; and a control unit (104). The polarization-splitting element (125) of the measurement arm is configured to simultaneously send, over each of the first and second detection channels, respectively, a first and second polarized component (BS1, BS2) of the beam (BS) scattered by the sample, the polarization axes of the first and second polarized components being perpendicular. The control unit (104) is configured to determine, from signals corresponding to the polarized components detected in each of the detection channels as a function of time, at least two characteristic parameters of the dimensions of the nanoparticles., Selon un aspect, la présente description a pour objet un dispositif (100) de détermination de paramètres caractéristiques des dimensions de nanoparticules en suspension dans un liquide.Le dispositif (100) comprend des moyens d’émission lumineuse (101) configurée pour émettre un faisceau incident (Bi) polarisé linéairement selon un axe de polarisation (P1); une unité de détection (102) comprenant un bras de mesure (120) mobile en rotation autour d’un axe de rotation (∆), ladite unité de détection comprenant une première et une deuxième voies de détection (151, 161) séparées par un élément séparateur de polarisation (125) agencé sur ledit bras de mesure; un support d’échantillon fixe (103), configuré pour recevoir un contenant (10) à symétrie cylindrique dudit échantillon, un axe de symétrie du contenant étant confondu avec l’axe de rotation du bras de mesure; une unité de contrôle (104). L’élément séparateur de polarisation (125) du bras de mesure est configuré pour envoyer simultanément, sur chacune des première et deuxième voies de détection, respectivement une première et une deuxième composantes polarisées (BS1, BS2) du faisceau (BS) diffusé par l’échantillon, les axes de polarisation des première et deuxième composantes polarisées étant perpendiculaires.L’unité de contrôle (104) est configurée pour déterminer, à partir de signaux correspondant aux composantes polarisées détectées sur chacune des voies de détection en fonction du temps, au moins deux paramètres caractéristiques des dimensions des nanoparticules.

International audience; In this study, an original method of macromolecular design was used to develop a hyaluronidase‐1 (HYAL1) inhibitor from its principal substrate, hyaluronic acid (HA). HA‐based nanoparticles (HA‐NP) were obtained by copolymer self‐assembly and their effects on HYAL1 activity were investigated by combining different analytical tools. Compared to HA, HA‐NP exhibited an enhanced stability against HYAL1 degradation while maintaining its interaction with HA receptors CD44 and aggrecan. HA‐NP displayed a strong and selective inhibition of HYAL1 activity and retarded the hydrolysis of higher molar mass HA in solution. A co‐nanoprecipitation process was used to formulate a range of hybrid nanoparticle samples, which demonstrated the specificity and efficiency of HA‐NP in HYAL1 inhibition.

In the emerging field of hybrid polymer/lipid vesicles, relatively few copolymers have been evaluated regarding their ability to form these structures and the resulting membrane properties have been scarcely studied. Here, we present the synthesis and self-assembly in solution of poly(dimethylsiloxane)-block-poly(ethylene oxide) diblock copolymers (PDMS-b-PEO). A library of different PDMS-b-PEO diblock copolymers was synthesized using ring-opening polymerization of hexamethylcyclotrisiloxane (D3) and further coupling with PEO chains via click chemistry. Self-assembly of the copolymers in water was studied using Dynamic Light Scattering (DLS), Static Light Scattering (SLS), Small Angle Neutron Scattering (SANS), and Cryo-Transmission Electron Microscopy (Cryo-TEM). Giant polymersomes obtained by electroformation present high toughness compared to those obtained from triblock copolymer in previous studies, for similar membrane thickness. Interestingly, these copolymers can be associated to phospholipids to form Giant Hybrid Unilamellar Vesicles (GHUV), preliminary investigations of their mechanical properties show that tough hybrid vesicles can be obtained.

In pharmaceutical technology, lipids and polymers are considered pillar excipients for the fabrication of most dosage forms, irrespective of the administration route. They play various roles ranging from support vehicles to release rate modifiers, stabilizers, solubilizers, permeation enhancers and transfection agents. Focusing on selected applications, which were discussed at the Annual Scientific Meeting of the Gattefossé Foundation 2018, this manuscript recapitulates the fundamental roles of these two important classes of excipients, either employed alone or in combination, and provides insight on their functional properties in various types of drug formulations. Emphasis is placed on oral formulations for the administration of active pharmaceutical ingredients with low aqueous solubilities or poor permeation properties. Additionally, this review article covers the use of lipids and polymers in the design of colloidal injectable delivery systems, and as substrates in additive manufacturing technologies for the production of tailor-made dosage forms., International Journal of Pharmaceutics, 558, ISSN:0378-5173, ISSN:1873-3476, ISSN:0378 -5173

International audience; Elastin-like polypeptides (ELPs) are biocompatible-engineered polypeptides, with promising interest in tissue engineering due to their intrinsic biological and physical properties, and their ease of production. The IKVAV (Ile-Lys-Val-Ala-Val) laminin-1 sequence has been shown to sustain neuron attachment and growth. In this study, the IKVAV adhesion sequence, or a scrambled VKAIV sequence, were incorporated by genetic engineering in the structure of an ELP, expressed in Escherichia coli and purified. The transition temperatures of the ELP-IKVAV and ELP-VKAIV were determined to be 23 °C. Although the phase transition was fully reversible for ELP-VKAIV, we observed an irreversible aggregation for ELP-IKVAV. The corresponding aggregates shared some characteristics with amyloid-like polypeptides. The two ELPs were then reacted with functionalized polyethylene glycol (PEG) to form hydrogels. These hydrogels were characterized for rheological properties, tested with cultures of rat primary sensory neurons, and implanted subcutaneously in mice for 4 weeks. Sensory neurons cultured on high IKVAV concentration hydrogels (20%) formed longer neurite than those of neurons grown on hydrogels containing the scrambled IKVAV sequence. Finally, in vivo evaluation showed the absence of detectable inflammation. In conclusion, this functionalized ELP-IKVAV biomaterial shows interesting properties for tissue engineering requiring neurotization.

International audience; PEGylated magnetic iron oxide nanoparticles (IONPs) were synthesised with the aim to provide proof of concept results of remote cancer cell killing by magnetic fluid hyperthermia. The IONPs were produced by the polyol synthetic route also called “forced hydrolysis pathway” yielding highly superparamagnetic, readily-dispersible, and biocompatible IONPs. As shown previously, adjusting parameters of the reaction led to either monocore or multicore IONPs, with on-demand morphology and magnetic properties. Polyethylene glycol (PEG) was grafted onto the nanoparticles in a single final step, using a phosphonic acid-terminated PEG synthesised separately, a strategy named “convergent”. The magnetic properties of the IONPs were preserved in physiological media thanks to this biocompatible shell. The interaction of the PEGylated IONPs with a glioblastoma cell line was studied, from the stability of IONPs in appropriate cell culture medium to the remotely magnetically triggered cell death. Cellular internalisation of the IONPs was studied, along with their fate after application of an alternating magnetic field (AMF). This investigation highlights the superior efficiency of multicore (nanoflowers) vs monocore (nanospheres) IONPs for magnetic hyperthermia, leading to 80 % cancer cells death in medically translatable conditions.

Interactions of polymers with the biological environments Polymers have gradually entered into the composition of biomaterials or drug formulations with respect to their biocompatible and biodegradable features, but also to their structural versatility. A new era in the biomedical fields has nevertheless begun, where polymers are no longer passive components but actors that interact directly with the biological environments. This article covers the cases of polymers that are intrinsically bioactive, but also those coupled to ligands or biomolecules, or responding to endo-or exogenous stimuli. Then a new approach to the synthesis of polymers with high added value by biotechnology is mentioned., Les polymères sont progressivement entrés dans la composition des biomatériaux ou des formulations médicamenteuses au regard de leurs caractères biocompatibles, biodégradables mais également de leur polyvalence structurelle. Une nouvelle ère dans les domaines biomédicaux est néanmoins largement amorcée, où les polymères ne sont plus des composants passifs, mais de véritables acteurs pour interagir directement avec les interlocuteurs des milieux biologiques. Cet article aborde les cas des polymères intrinsèquement bioactifs, mais aussi des polymères couplés à des ligands ou des biomolécules, ou encore de ceux répondant à des stimuli endo-ou exogènes. Puis une nouvelle approche de synthèse de polymères à haute valeur ajoutée par voie biotechnologique est mentionnée.

Hybrid copolymer/lipid vesicle are recently developed self-assembled structures that could present biocompatibility and biofunctionality of liposomes, as well as robustness, low permeability and functionality variability conferred by the copolymer chains. However, to date, physical and molecular parameters governing copolymer/lipid phase separation in these hybrid membranes are not well understood. In this work, we studied in detail the formation and phase separation in the membranes of both Giant Unilamellar Hybrid Vesicles(GHUVs) and Large Unilamellar Hybrid Vesicles (LHUVs) obtained from the mixture of phospholipids in the fluid (liquid disordered) or gel state (solid ordered) with various copolymers based on poly(dimethylsiloxane) (PDMS) and poly(ethylene glycol) (PEO) with different architectures (grafted, triblock) and molar masses. For GHUVs, phase separation at the micron scale and nanoscale was evaluated through confocal microscopy, and Fluorescence lifetime imaging microscopy technique (FLIM) respectively, where as acombination of Small angle neutron scattering (SANS), Cryo-transmission electron microscopy (Cryo-TEM) and Time-resolved Förster resonance energy transfer (TR-FRET) techniques was used for LHUVs. We demonstrate that the lipid/polymer fraction, lipid physical state, and the line tension at lipid polymer/lipid boundaries which can be finely modulated by the molar mass and architecture of the copolymer are important factors that govern the formation and structuration of hybrid vesicles. We also evidence that elasticity ofthe hybrid membrane can be modulated via the lipid polymer composition, through the use of micropipettes techniques., Les vésicules hybrides polymère/lipides sont des structures récemment développées dans la littérature. Idéalement, celles-ci peuvent présenter la biocompatibilité et la biofonctionnalité des liposomes, ainsi que la robustesse, la faible perméabilité et la versatilité de fonctionnalisation chimique conférées par les chaînes de copolymères. Cependant, à ce jour, les facteurs régissant la séparation des phases dans ces membranes hybrides ne sont pas bien compris. Dans ce travail, nous avons étudié en détail la formation et la séparation de phases dans les membranes de vésicules géantes (GHUVs) et de taille nanométriques(100nm) (LHUVs) constituées de phospholipides en phase fluide ou gel et de copolymères à base de poly (diméthylsiloxane) et de poly (éthylène glycol). Différentes architectures(greffée, tribloc) et masses molaires ont été utilisées. La séparation de phase a été étudiée sur les vésicules géantes à l’échelle micrométrique et nanométrique respectivement par microscopie confocale et imagerie de fluorescence résolue en temps (FLIM), tandis que pour les LHUVs, différentes techniques comme la diffusion de neutrons, la Cryo-microscopie et la spectroscopie de fluorescence résolue dans le temps ont été combinées. Nous avons pu montrer que la fraction lipide/polymère, l'état physique du lipide et la tension de la ligne aux interfaces lipide/polymère modulable par la masse molaire et l'architecture du copolymère sont les facteurs importants régissant la formation et la structuration des vésicules hybrides. Enfin, nous avons montré que les propriétés élastiques de la membrane peuvent être modulées via la composition polymère lipide.

The present invention relates to a sub-micrometer material formed by a silica shell encasing a core of superparamagnetic wax, to the production method thereof and to the uses of same, in particular for the magnetically stimulated delivery of substances of interest., La présente invention est relative à un matériau sub-micrométrique constitué d'une enveloppe de silice renfermant un cœur de cire superparamagnétique, à son procédé de préparation et à ses utilisations, notamment pour la délivrance magnéto-stimulée de substances d'intérêt.

International audience; With specialist knowledge of polymer-based, self-assembled nanoparticles, the Laboratoire de Chimie des Polymères Organiques shares developments in polymer synthesis and polymer materials. We are a group of 5 tenured academic researchers and about 15 non-permanent researchers in the Laboratoire de Chimie des Polymères Organiques, a joint research unit of CNRS, University of Bordeaux, and Bordeaux National Polytechnic Institute, dedicated to polymer synthesis and polymer materials. More precisely, our group develops polymer-based self-assembled nanoparticles with high loading rates of active pharmaceutical ingredient (anticancer drugs, peptides, proteins...), multi-modal labelling (MRI, NIR...) and targeting (e.g. mAb). Our know-how includes the synthesis of biocompatible polymers such as polypeptides (by chemical synthesis or recombinant route), polysacharrides, and their combination as copolymers. We have a more than 1 decade experience in the design of multifunctional polymer vesicles called "polymersomes" loaded with drugs, iron oxide nanoparticles, grafted to antibodies, and several patents including one licensed to a pharmaceutical company located in Lyon (Adocia). We have some experience as participant in European projects, including a FP7 large NMP project (NANOTHER), which led to very promising results and productive interactions with biomedical companies, and we are now seeking to be active partners of a new H2020 project on nanomedicine.

Si l'idée de disperser des charges inorganiques dans un cristal liquide thermotrope remonte aux années 70,[1] sa réalisation reste d'actualité: le dopage de cristaux liquides organiques par des charges inorganiques permettrait en effet d'améliorer leurs caractéristiques tant diélectriques[2] que magnétiques.[3] En mesurant la biréfringence magnéto-induite, nous observons la « transition de Fredericksz » du cristal liquide 5CB (4-cyano-4'-pentylbiphenyl) soumis d'un côté à un ancrage homéotrope à la surface et de l'autre en volume à l'orientation magnétique planaire.[4] Cette mesure de biréfringence a servi aussi à B. Lemaire à Orsay pour mettre en évidence la transition du paramètre d'ordre S2 de suspensions inorganiques de goethite alpha-FeOOH en phase isotrope entre une valeur non nulle positive à bas champ H et négative à champ fort, interprétée comme la compétition entre l'énergie d'un moment permanent résiduel de surface parallèle aux bâtonnets et celle du moment induit perpendiculaire.[5] En modifiant les conditions de synthèse, nous obtenons des échantillons de longueurs variables de 500 à 15 nm, et nous montrons que la croissance des bâtonnets suit un mécanisme dit « agrégation orientée » des germes de ferrihydrite.[6] Le dopage par des ions paramagnétiques (Co2+, Ni2+) permet d'agir sur les valeurs des moments permanent et induit tels que mesurés par les différentes techniques (magnétométrie, biréfringence, diffusion anisotrope des neutrons) pour une série d'échantillons. Nous discuterons du dopage d'un cristal liquide par ces nanoparticules allongées afin d'abaisser le champ seuil de Fredericksz. Références 1. F. Brochard & P-G. De Gennes, J. Phys. (France) 31 691-708 (1970) 2. Y. Reznikov & A. Buchnev, Molec. Cryst. & Liq Cryst. 453:227-237 (2006) 3. C. Da Cruz, O. Sandre, V. Cabuil, J. Phys. Chem. B 109(30), 14292 (2005) 4. M. Konerackf, V. Kellnerova, P. Kopcansky, T. Kuczynski, JMag.Mag.Mat.140-144, 1455 (1995) 5. B.J. Lemaire, P. Davidson, J. Ferré, J.P. Jamet, D. Petermann, P. Panine, I. Dozov, and J.-P. Jolivet Eur. Phys. J. E 13, 291–308 (2004) 6. A. Abou-Hassan, O. Sandre, S. Neveu, V. Cabuil, Angew. Ch. 48 1-5 (2009)

L'idée de l'association de charges inorganiques avec un cristal liquide organique thermotrope remonte au modèle de Brochard et De Gennes dans les années 80, mais elle est toujours d'actualité parmi les expérimentateurs : le dopage de cristaux liquides organiques par des nanoparticules permettrait en effet d'améliorer leurs caractéristiques tant diélectriques que magnétiques [1]. Un des effets du dopage serait d'abaisser le champ seuil (électrique ou magnétique) de la transition de Fredericksz observée quand un cristal liquide est soumis aux orientations antagonistes (homéotrope versus planaire) de l'ancrage sur la surface de la cuve et de l'orientation induite en volume par le champ [2]. Même en l'absence de nanoparticules magnétiques, le diamagnétisme naturel des molécules aromatiques qui composent le 4-cyano-4'-pentylbiphenyl (5CB) peut être mesuré avec un dispositif de biréfringence [3]. Ce même dispositif que celui que nous utilisons couramment pour mesurer la biréfringence magnéto-induite des nanoparticules magnétiques (ferrofluides) nous a permis : (i) de déceler précisément le seuil de la transition de Fredericksz pour le 5CB pur (0.1 Tesla pour une cuve de 100µm) ; (ii) de suivre une autre transition d'orientation mise en évidence par Bruno Lemaire et coll. [4] avec un autre type de nématique, cette fois-ci purement inorganique, la goethite Α-FeOOH, qui peut facilement être synthétisée en laboratoire [5]. Cette transition repose sur la compétition entre le moment magnétique permanent parallèle aux bâtonnets de goethite et leur moment induit qui lui est perpendiculaire. Dans cette communication, nous tenterons d'expliquer pourquoi il serait plus judicieux de doper un cristal liquide thermotrope par des nanparticules allongées plutôt qu'isotropes afin d'abaisser les champs magnétiques nécessaires à réorienter les domaines. Nous donnerons aussi des résultats préliminaires de la transition d'orientation magnétique avec de la goethite dopée par des ions paramagnétiques. Références : [1] Ferroelectric Particles in Liquid Crystals: Recent Frontiers Anatoliy Glushchenko, Chae Il Cheon, John West, Fenghua Li, Ebru Büyüktanir, Yuri Reznikov and Alexander Buchnev Molecular Crystals and Liquid Crystals, 453:227-237, 2006 [2] Study of magnetic Fredericksz transition in ferronematic M. Konerackf, V. Kellnerova, Kopcansky, T. Kuczynski, Journal of Magnetism and Magnetic Materials 140-144 (1995) 1455- 1456 [3] Magnetic birefringence in a liquid crystal: An experiment for the advanced undergraduate laboratory, Thomas Moses, Brian Durall, and Gregory Frankowiak Am. J. Phys. 68 (3), March 2000 [4] Physical properties of aqueous suspensions of goethite (α-FeOOH) nanorods Part I: In the isotropic phase B.J. Lemaire, P. Davidson, J. Ferré, J.P. Jamet, D. Petermann, P. Panine, I. Dozov, and J.-P. Jolivet Eur. Phys. J. E 13, 291–308 (2004) [5] Synthesis of acicular Α-FeOOH particles at a very high pH, S. Krehula, S. Popovic, S. Music, Materials Letters 54 (2002) 108–113

We are interested to in a new type of composite material based on the association of a thermosensitive polymer, poly(N-isopropylacrylamide) noted PNIPAM and a colloidal dispersion of magnetic iron oxide nanoparticles called an “ionic ferrofluid”. On the one hand, PNIPAM exhibits a volume phase transition at the threshold temperature 32°C called LCST (Lower Critical Solution Temperature); on the other hand, the nanoparticles made of maghemite (Γ-Fe2O3) bring different properties among which superparamagnetism and the possibility to induce heating at distance under radiofrenquency waves. Thus combing the two components in the same formulation could lead to capsules that could deliver a drug on-demand. This design is challenging because of unfavourable interactions between the poorly polar network of PNIPAM (even hydrophobic above the LCST) and the highly polar magnetic oxide nanoparticles, which are stabilized against aggregation at pH 7 by the use of surface electrostaticaly charged ligands sodium citrate. The macroscopic study of gels chemically cross-linked in the presence of a ferrofluid reveals that with pure PNIPAM almost all the nanoparticles are released in the surrounding. On the contrary, the magnetic nanoparticles can be retained in gels based on a copolymerization of NIPAM with the mush more polar polymer poly(acrylamide) PAM. To reach this goal, the copolymer should not be simply statistical as the swelling transition would loses both its sharpness and its amplitude. By studying the interactions between the magnetic nanoparticles and linear PAM chains, we show that the concentration of sodium citrate needs to be sufficiently low so that the citrate ligands desorb and can be replaced by PAM chains adsorption at the iron oxide surface. Dealing with gels, we used this phenomenon to stop the release of nanoparticles outside the gel by creating a semi-interpenetrated network of NIPAM and PAM. More precisely, linear hydrophilic chains of PAM are adsorbed on the nanoparticles creating small clusters (about 60-100 nm in size) which are sterically trapped within the meshsize of NIPAM. This type of system permits us to retain more than half of the introduced nanoparticles inside the gels. The swelling volume of theses nanocomposites gels are followed both at a macroscopic and nanoscopic scales, by Small Angle Neutron Scattering (SANS) experiments using the nanoparticles as internal structure probes. Passing through the volume transition of the gel matrix, the internal structure of the magnetic clusters undergoes a collapse completely reversible when the temperature is lowered back.

During the seventies when the main properties of magnetic fluids were first understood, (superparamagnetism, birefringence, hydrodynamics instabilities...) theoreticians [1] have imagined the possible advantages of a ferrofluid with a thermotropic nematic liquid crystal (LC) as a solvent. Such a “ferronematic” would indeed combine the properties of two systems which become optically anisotropic (birefringent) under electrical and magnetic fields. The today widely used liquid crystals displays (LCDs) are based on the transition between transparent and opaque state of LCs, controlled by electric fields. For certain applications, magnetic fields could be used instead if we could lower down the threshold magnetic field intensity Hc of the so called Fredericks transition arising from the competition between alignment of LC molecules by surfaces and by an applied magnetic field. This idea motivated our experimental study of dispersion of nanoparticles made of maghemite iron oxide (Γ-Fe2O3) and 5-CB, one of the most standard nematic LCs which is convenient due to its nematic-isotropic temperature (TN-I=35°C) slightly above room temperature. However, we found that a true (monophasic) ferrofluid with 5-CB as solvent can be obtained only in the isotropic phase (above TN-I), whereas in the nematic state, the system separates between two phases: one the one hand magnetic microdroplets made of a high concentration of magnetic nanoparticles (about 18 vol% from SAXS measurements) in isotropic 5-CB and on the other hand a non magnetic 5-CB nematic matrix [2]. This phenomenon was explained by the thermodynamic laws for a ternary system (nanoparticles – LC – surfactant). Two aspect of these highly magnetic droplets in a LC host matrix where studied : i) their influence on the threshold field Hc of the Fredericks transition of a 5-CB layer sandwitched between two plates with homeotropic alignment conditions; ii) their strong ellipsoidal deformation under a magnetic field of low intensity, which – by analogy with ferrofluid droplets in a non magnetic liquid – provides an experimental measurement of the interfacial tension and tentatively of the anchoring energy of LC molecules onto nanoparticles [3]. ___________________________________________________ [1] F. Brochard, P. G. de Gennes, J. Phys. (Paris), 1970, 31, 691. [2] C. Da Cruz, O. Sandre, V. Cabuil, Journal of Phyical Chemistry B (2005) 109, 14292. [3] J. Deseigne, report of ESPCI engineering school short training period (March 2006).

National audience

Actuellement les recherches s'intensifient sur des matériaux nanocomposites ‘mous' qui allient les propriétés d'une matrice polymère (faible module élastique, sensibilité au milieu, à la température, ...) avec celles de nanoparticules inorganiques aux propriétés physiques particulières (catalytiques, optiques, magnétiques..). Ainsi les industriels ont-ils commencé à réfléchir aux possibilités apportées par de tels matériaux : colle chargée en nanoparticules magnétiques qui sèche par un chauffage inductif modéré et se dégrade dans un champ magnétique plus fort (pour le démontage des pièces automobiles en fin de vie), des elastomères dont le module serait ajustable par un champ magnétique (pour des applications anti-vibratoires), des films minces guidant la lumière visible ou les micro-ondes (pour la réalisation d'éléments optiques, d'antennes),... Des applications biomédicales sont aussi visées, par exemple dans le domaine du ‘drug delivery' qui nécessite des objets de taille typiquement 200 nm, dispersables dans le sang, et pouvant libérer une substance suite à un stimulus magnétique. Dans ce séminaire on présentera quelques systèmes de type ‘nanocomposites magnétiques' qui ont en commun d'être préparés en jouant sur les différentes interactions disponibles entre des polymères soit complètement hydrophiles, soit auto-associatifs dans l'eau, et les nanoparticules magnétiques dont les suspensions stables dans l'eau ou d'autres solvants sont appelées ‘ferrofluides'. Le cas d'une simple adsorption des chaînes sur les nanoparticules sera illustré par des exemples d'hydrogels à base de poly-acrylamide, emprisonnant les nanoparticules de manière plus ou moins efficace selon la salinité. La recherche d'hydrogels à la fois magnétiques et thermsensibles a conduit à la réalisation de réseaux semi-interpénétrés de poly-N-isopropylacrylamide (polymère à LCST) et de chaînes hydrophiles complexantes pour l'oxyde de fer. La version ‘dispersée' de ce type de réseaux sera présentée avec des minigels magnétiques dont on étudie les mêmes propriétés (gonflement, thermosenbilité, ...) que leur équivalent ‘bulk'. Puis on s'intéressera à d'autres objets dispersés mettant en juin des interactions plus fortes entre les nanoparticules et des copolymères di-blocs : d'une part l'interaction hydrophobe avec des di-blocs amphiphiles à structure ‘rod-coil' formant des vésicules (collaboration avec Sébastien Lecommandoux de l'ENSCP Bordeaux) ; d'autre part l'interaction électrostatique avec des diblocs totalement hydrophiles neutres-chargés formant des coacervats (micro-phase dispersée sous forme d'agrégats mixtes de taille limitée) en présence de nanoparticules de charge opposée (collaboration avec Jean-François Berret, MSC Paris 7). Pour ces différents systèmes, ce sont à la fois des mesures de diffusion des neutron et des images de (Cryo)TEM qui permettent de vérifier que les structures à l'échelle obtenues par auto-assemblage correspondent à l'idée que s'en faisait le physco-chimiste au moment de la formulation.

International audience; Novel magnetic nano-composites are obtained by the self-assembly in water of polypeptide-based di-block copolymers polybutadiene-b-poly(glutamic acid) combined with hydrophobically modified gamma-Fe2O3 nanoparticles. These hybrid supramolecular objects are either filled micelles (3-d) or hollow vesicles with a magnetic membrane (2-d), deformation of which under an applied magnetic field has been evidenced. These nanoparticles are also able to respond to stimuli such as pH and ionic strength due to the presence of the polypeptide block, thus forming what we called multi-responsive nanocapsules. These superparamagnetic hybrid self-assemblies offer attractive potentialities in biomedicine and biotechnology due to their dimensions (0.1-0.5 mu m) small enough to stay for some time in the blood circulation. and due to the properties brought about by the iron oxide nanoparticles: possible manipulation by an external magnetic field gradient, local heating by a radio-frequency field for cancer radio-therapy, labeling of organs to enhance the contrast in Magnetic Resonance Imaging.

Créés dans les années soixante pour des applications technologiques, les ferrofluides sont des solutions colloïdales de grains magnétiques nanométriques qui restent stables (c'est à dire monophasiques) quelle que soit l'intensité d'un champ magnétique appliqué. Parmi les procédés de synthèse existants, celui de R. Massart par co-précipitation de sels ioniques nous permet au LI2C de préparer couramment des ferrofluides dans divers milieux aqueux et dans des huiles, en adaptant la surface des nanoparticules, avec un certain contrôle des tailles des grains formés. Leur association avec des fluides complexes auto-associatifs a été envisagée assez tôt, dans le but de former des systèmes variés ayant une réponse en champ magnétique conférée par les nanoparticules. Citons par exemple les ferrosmectiques lyotropes qui sont le fruit d'une collaboration entre notre équipe et le LPMC du Collège de France. Dans le cas des macromolécules, les premiers travaux avec J. Bastide ont concerné les propriétés de séparation de phases du système nanoparticules – chaînes libres, par effet de déplétion. Auparavant, l'idée d'utiliser les nanoparticules magnétiques comme sondes rhéologiques locales grâce à l'utilisation de leurs propriétés magnéto-optiques avait déjà conduit J.-C. Bacri à disperser ces particules non plus dans un fluide visqueux simple, mais dans un gel physique comme la gélatine. La notion de « ferrogels » a été définie par M. Zrinyi de l'Université de Budapest comme l'association intime de nanoparticules magnétiques et de gels chimiques. Des hydrogels ont été utilisés principalement, car ce types d'élastomères gonflés d'eau sont suffisamment mous pour espérer un couplage entre l'aimantation et l'élasticité. Notre objectif actuel est de fabriquer des actionneurs magnétiques mous, qui répondraient en plus à la température ou au pH. Nous explorons différentes voies pour créer des ferrogels avec une réponse magnéto-élastique notable. Les gels polymères utilisés sont formés à base d'acrylamide, d'acrylate, ou de N-isopropylacrylamide, mais aussi de polysaccharides naturels (alginates). D'un point de vue fondamental, nous cherchons à relier la « structure hiérarchique nano-structurée » de tels ferrogels – en clair l'état de dispersion des nanoparticules à l'intérieur du maillage polymérique et leur capacité ou non à se mouvoir en translation ou en rotation – avec les propriétés macroscopiques comme le taux de gonflement par le solvant, le taux de relargage des particules ou le module élastique. La variation de ce dernier en présence d'un champ magnétique est aussi envisagée (phénomène de magnéto-striction). La difficulté d'utiliser des hydrogels comme matrices polymères, mais aussi ce qui fait leur richesse, provient de leur sensibilité à la composition du milieu aqueux, comme certains effets de sel qui se sont présentés. Pour comprendre le rôle des interactions nanoparticules – polymères dans la structure des réseaux des ferrogels, nous avons étudié un système simplifié de chaînes libres non réticulées. Par ailleurs dans un but un peu appliqué, nous nous sommes intéressés non plus à des systèmes massifs mais à des objets dispersés, préparés à partir de ferrofluides et de polymères. Il s'agit d'une part de microgels de tailles comprises entre 100 nm et 10 µm. De même nature chimique que les ferrogels macroscopiques, ils en possèdent aussi la faculté de gonflement dans l'eau, mais avec une dynamique beaucoup plus rapide. D'autre part nous étudions aussi en collaboration avec S. Lecommandoux de l'ENSCPB à Bordeaux des vésicules polymériques pH-sensibles et magnétiques. Leur membrane constituée d'un copolymère di-bloc a en effet pu être dopée avec des nanoparticules magnétiques. Ces polymérosomes magnétiques restent fluides et se déforment sous un champ de faible intensité (0.1 Tesla). Ces deux derniers types d'objets nanoscopiques pourraient avoir des applications dans le tri de produits biologiques, le « drug-delivery », le marquage de cellules pour l'IRM, ...

International audience; We demonstrate that simultaneous second-harmonic generation (SHG) and two-photon excited fluorescence (TPEF) can be used to rapidly image membranes labeled with a lipophilic styryl dye. We have developed a model based on the theory of phased-array antennas which shows that the SHG radiation is highly structured and can be roughly of the same power as TPEF. This model provides a definition of a SHG cross-section which can be directly compared to the TPEF cross-section.

International audience; We present a detailed analysis of the generation of second-harmonic radiation from biological membranes labeled with a styryl dye. In particular, we consider the high-numerical-aperture limit appropriate to high-resolution microscopy in which an excitation beam is tightly focused from the side onto a membrane surface. In this limit the active surface area that contributes to second-harmonic generation (SHG) depends only on the tightness of the beam focus and the SHG radiation is confined by phase matching into two well-defined off-axis lobes. We derive expressions for the SHG radiation power, angular distribution, and polarization dependence in the cases of ideal or nonideal molecular alignment in the membrane and uniaxiality of the molecular hyperpolarizability. We define an SHG cross section similar to that used in two-photon-excited fluorescence (TPEF) to permit direct comparison of the two imaging modalities. Finally, we corroborate our results with experiments based on the excitation of a styryl dye in giant unilamellar vesicles with a mode-locked Ti:sapphire laser.