Olivier Sandre

Doxorubicin Loaded Magnetic Polymersomes: Theranostic Nanocarriers for MR Imaging and Magneto-Chemotherapy

Hydrophobically modified maghemite (γ-Fe(2)O(3)) nanoparticles were encapsulated within the membrane of poly(trimethylene carbonate)-b-poly(l-glutamic acid) (PTMC-b-PGA) block copolymer vesicles using a nanoprecipitation process. This formation method gives simple access to highly magnetic nanoparticles (MNPs) (loaded up to 70 wt %) together with good control over the vesicles size (100-400 nm). The simultaneous loading of maghemite nanoparticles and doxorubicin was also achieved by nanoprecipitation. The deformation of the vesicle membrane under an applied magnetic field has been evidenced by small angle neutron scattering. These superparamagnetic hybrid self-assemblies display enhanced contrast properties that open potential applications for magnetic resonance imaging. They can also be guided in a magnetic field gradient. The feasibility of controlled drug release by radio frequency magnetic hyperthermia was demonstrated in the case of encapsulated doxorubicin molecules, showing the viability of the concept of magneto-chemotherapy. These magnetic polymersomes can be used as efficient multifunctional nanocarriers for combined therapy and imaging.

Cascades of Transient Pores in Giant Vesicles: Line Tension and Transport

Under ordinary circumstances, the membrane tension of a giant unilamellar vesicle is essentially nil. Using visible light, we stretch the vesicles, increasing the membrane tension until the membrane responds by the sudden opening of a large pore (several micrometers in size). Only a single pore is observed at a time in a given vesicle. However, a cascade of transient pores appear, up to 30-40 in succession, in the same vesicle. These pores are transient: they reseal within a few seconds as the inner liquid leaks out. The membrane tension, which is the driving force for pore opening, is relaxed with the opening of a pore and the leakage of the inner liquid; the line tension of the pores edge is then able to drive the closure of a pore. We use fluorescent membrane probes and real-time videomicroscopy to study the dynamics of the pores. These can be visualized only if the vesicles are prepared in a viscous solution to slow down the leakout of the internal liquid. From measurements of the closure velocity of the pores, we are able to infer the line tension,. We have studied the effect of the shape of inclusion molecules on. Cholesterol, which can be modeled as an inverted cone-shaped molecule, increases the line tension when incorporated into the bilayers. Conversely, addition of cone-shaped detergents reduces. The effect of some detergents can be dramatic, reducing by two orders of magnitude, and increasing pore lifetimes up to several minutes. We give some examples of transport through transient pores and present a rough measurement of the leakout velocity of the inner liquid through a pore. We discuss how our results can be extended to less viscous aqueous solutions which are more relevant for biological systems and biotechnological applications.

Magnetic responsive polymer composite materials

Magnetic responsive materials are the topic of intense research due to their potential breakthrough applications in the biomedical, coatings, microfluidics and microelectronics fields. By merging magnetic and polymer materials one can obtain composites with exceptional magnetic responsive features. Magnetic actuation provides unique capabilities as it can be spatially and temporally controlled, and can additionally be operated externally to the system, providing a non-invasive approach to remote control. We identified three classes of magnetic responsive composite materials, according to their activation mode and intended applications, which can be defined by the following aspects. (A) Their ability to be deformed (stretching, bending, rotation) upon exposure to a magnetic field. (B) The possibility of remotely dragging them to a targeted area, called magnetic guidance, which is particularly interesting for biomedical applications, including cell and biomolecule guidance and separation

Coherent Scattering in Multi-Harmonic Light Microscopy

By focusing a pulsed laser beam into a sample, harmonic up-conversion can be generated as well as multi-photon excited fluorescence. Whereas multi-photon excited fluorescence microscopy is well established, the use of multi-harmonic generation for three-dimensional image contrast is very recent. Both techniques can provide similar resolution and, for adequate radiating source density, comparable signal levels, allowing them to be combined in a single versatile instrument. However, harmonic generation differs fundamentally from fluorescence generation in that it is coherent and produces radiation patterns that are highly sensitive to phase. As such, multi-harmonic generation microscopy provides a unique window into molecular spatial organization that is inaccessible to fluorescence.

Membrane imaging by simultaneous second-harmonic generation and two-photon microscopy

We demonstrate that simultaneous second-harmonic generation (SHG) and two-photon-excited fluorescence (TPEF) can be used to rapidly image biological membranes labeled with a styryl dye. The SHG power is made compatible with the TPEF power by use of near-resonance excitation, in accord with a model based on the theory of phased-array antennas, which shows that the SHG radiation is highly structured. Because of its sensitivity to local asymmetry, SHG microscopy promises to be a powerful tool for the study of membrane dynamics.

Microfluidics in Inorganic Chemistry

The application of microfluidics in chemistry has gained significant importance in the recent years. Miniaturized chemistry platforms provide controlled fluid transport, rapid chemical reactions, and cost-saving advantages over conventional reactors. The advantages of microfluidics have been clearly established in the field of analytical and bioanalytical sciences and in the field of organic synthesis. It is less true in the field of inorganic chemistry and materials science; however in inorganic chemistry it has mostly been used for the separation and selective extraction of metal ions. Microfluidics has been used in materials science mainly for the improvement of nanoparticle synthesis, namely metal, metal oxide, and semiconductor nanoparticles. Microfluidic devices can also be used for the formulation of more advanced and sophisticated inorganic materials or hybrids.

Magnetic field triggered drug release from polymersomes for cancer therapeutics.

Local and temporal control of drug release has for long been a main focus in the development of novel drug carriers. Polymersomes, which can load both hydrophilic and hydrophobic species and, at the same time, be tailored to respond to a desired stimulus, have drawn much attention over the last decade. Here we describe polymersomes able to encapsulate up to 6% (w/w) of doxorubicin (DOX) together with 30% (w/w) of superparamagnetic iron oxide nanoparticles (USPIO; γ-Fe2O3). Upon internalization in HeLa cells and when a high frequency AC magnetic field (14mT at 750kHz) was applied, the developed delivery system elicited an 18% increase in cell toxicity, associated with augmented DOX release kinetics. In order to ensure that the observed cytotoxicity arose from the increased doxorubicin release and not from a pure magnetic hyperthermia effect, polymersomes loaded with magnetic nanoparticles alone were also tested. In this case, no increased toxicity was observed. We hypothesize that the magnetic field is inducing a very local hyperthermia effect at the level of the polymersome membrane, increasing drug release. This approach opens new perspectives in the development of smart delivery systems able to release drug upon demand and therefore, improving treatment control.

Fundamentals and advances in magnetic hyperthermia

Nowadays, magnetic hyperthermia constitutes a complementary approach to cancer treatment. The use of magnetic particles as heating mediators, proposed in the 1950s, provides a novel strategy for improving tumor treatment and, consequently, patient quality of life. This review reports a broad overview about several aspects of magnetic hyperthermia addressing new perspectives and the progress on relevant features such as the ad hoc preparation of magnetic nanoparticles, physical modeling of magnetic heating, methods to determine the heat dissipation power of magnetic colloids including the development of experimental apparatus and the influence of biological matrices on the heating efficiency.

Recent trends in the tuning of polymersomes' membrane properties

Abstract.“Polymersomes” are vesicular structures made from the self-assembly of block copolymers. Such structures present outstanding interest for different applications such as micro- or nano-reactor, drug release or can simply be used as tool for understanding basic biological mechanisms. The use of polymersomes in such applications is strongly related to the way their membrane properties are controlled and tuned either by a precise molecular design of the constituting block or by addition of specific components inside the membrane (formulation approaches). Typical membrane properties of polymersomes obtained from the self-assembly of “coil coil” block copolymer since the end of the nineties will be first briefly reviewed and compared to those of their lipidic analogues, named liposomes. Therefore the different approaches able to modulate their permeability, mechanical properties or ability to release loaded drugs, using macromolecular engineering or formulations, are detailed. To conclude, the most recent advances to modulate the polymersomes’ properties and systems that appear very promising especially for biomedical application or for the development of complex and bio-mimetic structures are presented.

Transient pores in stretched vesicles: role of leak-out

We have visualized macroscopic transient pores in mechanically stretched giant vesicles. They can be observed only if the vesicles are prepared in a viscous solution to slow down the leak-out of the internal liquid. We study here theoretically the full dynamics of growth (driven by surface tension) and closure (driven by line tension) of these large pores. We write two coupled equations of the time evolution of the radii r(t) of the hole and R(t) of the vesicle, which both act on the release of the membrane tension. We find four periods in the life of a transient pore: (I) exponential growth of the young pore; (II) stop of the growth at a maximum radius rm; (III) slow closure limited by the leak-out; (IV) fast closure below a critical radius, when leak-out becomes negligible. Ultimately the membrane is completely resealed.Notationdmembrane thicknessEsurface stretching modulusKbHelfrich bending constantQleak-out fluxrpore radiusripore radius at nucleationrcpore radius at zero tensionrLcharacteristic radius of leak-outrmradius at maximum (II)r23pore radius at cross-over between (II) and (III)r34pore radius at cross-over between (III) and (IV)Rvesicle radiusRiinitial vesicle radiusR0vesicle radius at zero tensionVLleak-out velocityV3slow closure velocity limited by leak-out (III)V4fast closure velocity at end (IV)η2lipid viscosityηssurface viscosityη0viscosity of solutionσsurface tensionσ0surface tension before pore openingτrise time of pore growth (I)Jline tension