Acronyme du projet/ Acronym of the project
Detailed Scientific projects
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- Bu səhifədəki naviqasiya:
- Nano-drugs for severe diseases (leader: Patrick Couvreur, PCPB/Univ. Paris 11)
- Nanophotonics : Nano-objects for energy control (leader : Jean-Jacques Greffet, LCFIO/IOGS)
7.4.Detailed Scientific projectsQuantum and Spin-based nanoelectronics (leader: Frédéric Nguyen Van Dau, Thales RT)Partners:
State of the art: Spintronics is the research field underlying the 2007 Nobel Prize in Physics attributed to Albert Fert and Peter Grünberg, in which one develops electronic functions based on the electron spin, whereas classical electronics is based on the use of the electron charge. This domain was initiated by the discovery of several new physical effects such as giant magnetoresistance (GMR), spin dependent tunneling (TMR) and spin transfer. Of course, these developments were made possible through important progress achieved in the domain of material synthesis which has allowed the growth of heterostructures and nanostructures combining magnetic and non magnetic metals, ultrathin insulating barriers, and more recently semiconductors and organic materials. Three large areas of application have been already impacted by the development of spintronics: • The domain of the magnetic recording with the read heads of hard disks • The magnetic sensors for applications in professional as well as consumer products. • The electronic memories (MRAM) Current trends in the beyond CMOS domain: The potential transition towards massively-parallel computing systems as well as new non-Von-Neumann paradigms, such as neuromorphic architectures, has a large potential impact. Intrinsic non-volatility of spintronics technologies is a significant advantage in terms of power consumption. The radiation hardness of spintronics metal-based technologies is also an advantage, in particular with respect to aerospace applications. Finally, the coupling of spin information with optics could open the way to its transmission by optical links. Whereas five years ago, the nanoelectronic domain consisted in 7-8 emerging technologies (molecular electronics, spintronics, resonant tunnelling diodes, single electron electronics, rapid single flux quantum logic, wave interference devices, ...) being developed in parallel, there is a general trend to develop now hybrid approaches in order to try to take advantages of multifunctionality. This has led in particular to the development of molecular spintronics, spintronics with semi-conductors and spintronics using carbon-based materials (carbon nanotubes, graphene). Several partners of this project are being very active in the exploration of these three domains. In addition, multiferroic materials combining magnetic and ferroic orders are being studied with the aim to demonstrate a writing function of a magnetic element by an electric field. Partners of this flag-ship project are also working on concepts of memristors with a first objective to obtain a proof of concept.
The US Nanoelectronics Research Initiative14 is a consortium of companies in the Semiconductor Industry Association, which seeks to accelerate research in nanoelectronics for the benefit of the technology industry. Concentrated in U.S. universities with sponsorship shared by industry and state governments, the goal of NRI is to demonstrate novel computing devices capable of replacing the CMOS transistor as a logic switch in the 2020 timeframe. It is interesting to mention some of the projects, leaded by US academic nanotechnology centers, that have been co-funded by NRI and the National Science Foundation in 2009:
The vision for the Systems of Neuromorphic Adaptive Plastic Scalable Electronics (SyNAPSE) program funded by DARPA (approx. 10 M$) is to develop electronic neuromorphic machine technology that scales to biological levels.15 Scientific Objectives A strategic analysis of the present and near future situation in the nanoelectronic domain, based on both scientific and technical literature and international roadmaps (see for example ITRS16) leads to the following statements:
From these considerations, it becomes clear that the main scientific and technological challenge in this domain can be summarized as follows: we need a novel device concept and/or computation architecture to enable a novel scaling path. Around this central objective, we have held several scientific meetings in order to identify the strengths, weaknesses and complementarities of the partners in this research area, as well as domains where a strengthening of local synergies could contribute to establish a world leading position. From this analysis, four strategic approaches have been selected, on which we intend to focus funding at least during the first four years of the project. The selection criteria of these approaches are based on their potential to address at least one of the two following key objectives:
Components (e.g., transistors) variability, defects and energy requirements make it increasingly difficult to design reliable digital systems. The stringent energy constraints are already forcing chip manufacturers to rely on customization, progressively trading standard processors for heterogeneous multi-core systems, a combination of cores and custom accelerators. These accelerators are independent hardware blocks, and thus they make it possible and realistic to introduce different approaches in both computing and nanocomponents, in a non-disruptive manner. In a remarkable convergence of trends, a range of novel nanocomponents have been recently emerging, called memristive devices, with physical properties which are ideally compatible with the dense and efficient implementation of several alternative computing approaches, such as reconfigurable circuits, and neuromorphic circuits. Not only these nanocomponents can provide a solution, but their intrinsic properties, also open up new functionalities and applications. Memristors are non-linear tuneable and non-volatile electrical resistance. These properties directly implement the possibility to store information (memory), but also to dynamically modify this information according to the inputs (artificial synapses). Memristors can be implemented using very different materials (ferromagnets, ferroelectrics, organic materials : molecules and carbon nanotubes) and aggressively scaled-down thanks to their 2-terminal nature. Memristive behaviors rely on complex physical mechanisms (based on spin or charge) which are still to be studied and understood in details. In order to understand how to take advantage of these nanocomponents for novel designs, and conversely, in order to focus the research in physics on the nanocomponents with the most promising application potential, several research groups in physics (CNRS/Thales, CEA-IRAMIS), circuits and systems design (IEF, CEA-LIST, INRIA-Saclay) will tightly interact, iterating over nanocomponents and their potential applications. More specifically, we plan to:
This high-risk / high-potential research will notably benefit from the large spectrum of expertise at the material and device physics level available within the Labex Nano-Saclay, from the currently active projects (e.g. ANR PANINI, ANR NanoInnov SPIN, FP7 NABAB) coordinated by local partners, from fruitful transverse on-going collaborations and the dynamics of an ambitious ERC project (CNRS/Thales). Furthermore, it is noticeable that partners already hold 6 patents in this field, covering device concepts as well as learning techniques.
Most magnetic nanodevices rely upon the ferromagnetic order parameter and therefore are inherently non-volatile and radiation hard. Furthermore, the dissipation energy of magnetic processes can be orders of magnitude smaller than the CMOS power-delay product of similar size devices. As such, advances in spintronics will be crucial to continue progress in computation and data storage in the face of dramatic increases in power consumption in highly scaled CMOS devices. Until now, spintronics devices are relied on magnetic fields and currents, which still generate relatively high dissipation. A novel solution is emerging based on electric field (E) gating to control the magnetic state. This route has been uncovered very recently in DMS semiconductors, multiferroic and metals materials. The application of E-fields to actuate a magnetic response remains however not widespread and this new route requires a detailed understanding of E-activation in hybrid systems and multifunctional materials, thanks to advanced experimental studies and associated theoretical analyses. This will permit the significant improvement in efficiency, needed before this approach can be used in E-assisted spintronic devices. We propose to study this emerging field of using electric (E) fields in oxydes and Electrolyte/ferromagnetic hybrid systems as well as multiferroic materials and DMS. New routes will be explored for E-field control of nanomagnetic systems with the transformative goal to provide the scientific underpinnings of next generation energy efficient, ultrafast and ultrasmall magneto-electronic devices. Three main goals will be pursued:
Each of the members of the present consortium that gathers 7 leading groups (IEF, CNRS/Thales, CEA-SPEC, LPS, Polytechnique, ECP, LPN), has achieved pioneering works in magnetic nanodevices and they show complementary key expertises. A collaborative work is therefore expected to generate added value and to have a wide impact in terms of fundamental research, intellectual property and spintronics applications (memories, logic, sensors) beyond the limits of CMOS technology.
Devices and products based on the spintronics concepts have already been introduced on the market, and new developments are expected for the next few years. However, many fundamental issues are still to be addressed, particularly: the adaptability of spintronic devices to semi-conductors, the control of the polarization in TMR devices and the design of devices where the spin transport may be monitored and eventually controlled by external stimuli other than a magnetic field, such as light, electrical field, pressure… In order to address these issues and more importantly to gain insight into the physical mechanisms at the molecular level that turns out to be determinant, we propose to develop a “spin-based molecular engineering” approach in the perspective of creating new spintronic functionalities and innovative devices. Three objectives will be pursued:
Beyond the fundamental understanding underlying the phenomenon of spin-dependent transport in molecular systems at the single-molecule level, we expect to achieve the following goals within the next four years:
The molecular approach is multidisciplinary; the objectives are at the interface between chemistry, physics and nanoscience and need a tight collaboration between groups that possess complementary skills. Thus, chemists with expertise in molecular magnetism and surface science (ICMMO-CNRS/P11, SPCSI-CEA) and physicists specialists in spintronics (CNRS/Thales/P11, SPEC-CEA, SPCSI-CEA, IEF-CNRS/P11) will contribute together to create new molecular objects, process them at the nanoscale in order to perform the spin dependent transport studies. Simultaneously, the physical properties of as-synthesized objects will be probed by STM and by spin polarized STM (SPCSI-CEA ‘ERC starting grant’, LPN–CNRS). This is crucial to gain profound knowledge about the interplay between the nanoobject magnetic properties and its surrounding, which is at the basis of the understanding of the electrode/molecule interface. Electronic structure, magnetism and spin-polarized transport theoretical calculations (SPCSI-CEA) will be performed for the interpretation of experimental results as well as a unique tool to predict and propose new nano-materials and molecules with original magneto-transport properties.
Semiconducting nanowire (NW) have been widely studied but, these “naked” NWs are very sensitive to surface states and subject to aging. Indeed they are mostly dedicated to applications for high sensitivity sensors. The development of radial core shell nanowires is therefore of special interest for the potential use in nanoelectronics, as well as for studying one-dimensional (1D) physics. With its well-established properties in 2D heterostructures and intrinsically high electron mobility, GaAs/AlGaAs system is of particular interest to realize core-shell NWs. Furthermore, the NWs can be buried in an epitaxial undoped GaAs overgrowth, protecting them from oxidation. The standard technique to connect nanowires is to disperse them on a insulating substrate and to deposit contact pads on the top of the wire. The drawback of this technique is the influence of the substrate due to charge trapping which are difficult to control. Here the burying material is perfectly controlled and allow an easy contact on the NW has grown on the substrate. Finally a doped GaAs can be sandwiched between two insulating GaAs layer in the overgrowth layer. Contacting this doped layer allows to use it as an annular gate to control the charge density of the NW. Compatible with CMOS Technology, SiGe/Si core/shell nanowire (NW) devices are also promising candidates for the future generation MOSFETs providing better channel control and hole mobility. These core-shell devices can be exploited both as p- and n-type devices. Substantial increases in mobility could be achieved in modulation-doped core–shell structures in which, for example, a layer of i-Si separates the i-Ge core from a high-densitydopant layer. The research programme can be declined as follow:
Though a strong worldwide effort is currently made to understand and take advantage of the unique transport properties of graphene (high mobility, chirality of massless particles, Klein tunneling,…) the Plateau-de-Saclay area has the ambition to be a one of the leading consortia in both experimental and theoretical aspects of fundamental and applied research in this promising field likely to cover nanoelectronics, spintronics and thermoelectrics. We will emphasize on the control of the growth on large area compatible with an effective fabrication of devices using CVD and epitaxial growths. This experimental effort will come along with numerical simulations which will also be useful for semiconducting NWs. In particular, to investigate all potentialities of graphene-based devices, the consortium will develop a multiscale strategy that combines state-of-the-art ab initio calculations of the structure and electronic properties, and effective approaches suitable for self-consistent full-device simulation within atomistic tight-binding description and/or the continuous Dirac model. Such numerical approaches will lead to the construction of analytical and compact models of transistors/devices, to be transferred to the "Nanodesign" project for circuit simulation. Concerning fundamental transport properties, first principles theory is still in its beginning, and a strong effort is needed in order to develop truly predictive approaches. Besides the crucial role of contacts, effects like electron-phonon coupling, many-body effects, disorder, defects, functionalization, or interaction between objects have to be elucidated. We will profit from our experience in the ab initio calculation and from our insertion in the European Theoretical Spectroscopy Facility (ETSF, www.etsf.eu ), which is a pool of competence for the calculation of electronic excitations and transport.. This simulation activity will be conducted in strong interaction with the experiment activity of the consortium. Added value of the labex for this flagship project: These four strategic approaches have been selected for their potential to generate innovation on one hand, and because they represent domains in which the complementarities of expertise coming from the different partners can be exploited to reach a world class impact. For two of them, namely “Nanodesign” and “Molecular spintronics”, there is a high level of interdisciplinarity. It is difficult to attract funding from conventional agencies in the initial stages of such approaches, and we thus intend to use the labex funding to allow the partners to reach the credibility threshold. For the two other approaches, the main interest of bringing together these competencies is to allow reaching the necessary critical mass needed by the high ambition of their objectives in terms of impact. In this case, funding will be essentially used in order to consolidate this critical mass. Each of these four strategic approaches is expected to deliver complementary building block technological solutions on the route towards one single challenge: “need of a novel device concept and/or computation architecture to enable a novel scaling path”. During the lifetime of the labex project, we intend to monitor the orientations of these approaches, eventually inject new ones in order to ensure that our common challenge is adequately addressed. On another hand, for building block solutions that would appear to reach a sufficient maturity level, we will systematically team up with System-X IRT, other laboratories and companies for larger scale prototyping and integration.
STATE OF THE ART Although the introduction of nanotechnology in pharmacology (“nanomedicine”) has revolutionized the delivery of drugs, allowing the emergence of new treatments with improved specificity, it is certain that currently available nanomedicines have not been able to improve the activity of a large number of drugs used to fight cancer, infections or metabolic disorders. These failures are due to:
This explains the limited number of marketed nanomedicines, despite the large number of publications in the field. There is, therefore, an urgent need for new ideas to revolutionize drug delivery. A key issue is the introduction of better and safer (bio)materials for drug targeting purposes to load more efficiently and to release in a controlled manner a large number of challenging drugs, for which no effective delivery system is yet available. The aim of the project B of the labEX is to address those issues by developing two breakthrough original nanotechnologies:
The research project will benefit from the multidisciplinarity of the different partners. For instance, the physico-chemical concepts developed by partner 4 in order to be apprehensive about the “nucleation/growth” of the nanoparticles will be used to optimize the synthesis of the terpene-based nanoparticles and the statistical physics will allow to predict the interaction with the cell membranes. By the same way, the tools of the microfluidics (partners 7 and 3) and of the structural characterization (ie. by X-ray diffraction) (partners 4, 22 and 14) will also allow to have a better comprehension on the mechanisms of nanoparticles formation whereas interaction with cell membranes will be investigated with fluorescence/FRET (partner 2). Making nanoterpenes and nanoMOFs specific for the relevant biological targets (ie. cancer or infected cells) is another key for the success of the current project which needs molecular surface decoration of nanoparticles with specific ligands. This will be performed using advanced approaches in bioconjugate chemistry (partners 7 and 4) The current project should accelerate the discovery of safer and more efficient nanomedicines able to fight severe diseases, such as cancers and infections. It addresses a clear medical need and proposes a new research strategy in the general context of a significant decrease in the discovery of new drugs by the pharmaceutical industry. It is expected that our project will be able to translate research concepts into drug candidates for phase I clinical trials. OBJECTIVES OF THE PROJECT SCIENTIFIC PROGRAMME 1°/ The “terpenoylation” for the design of new nanomedicines Terpenoids (or isoprenoids) are a group of compounds that are extraordinary diverse in chemistry, structure and function. A wide range of terpenoids show, indeed, common beneficial traits that are related to their molecular structure: their double bonds are required for the physical deactivation of reactive oxygen species. As suggested earlier by Ourisson17, their lipophilic character and widespread presence in all living organisms has led to the hypothesis that the most primitive lipids involved in the formation of membranes were exclusively polyterpenoids. Thus, polyterpenoids appear to be preferred building blocks in nature, and this inspired our approach. Surprisingly, although numerous natural terpenoids are flexible and biocompatible biopolymers, possessing a wide range of physico-chemical characteristics able to adapt to a wide variety of biologically active compounds, they have never been used previously in the nanomedicine world for drug delivery and targeting purposes, except very recently by partner 7 who published for the first time in NanoLetters18 the design of squalene-based nanomedicines . We took, indeed, advantage of the dynamically folded conformation squalene (a triterpene) to link this natural lipid to gemcitabine, whose anticancer activity is limited by a short biological half-life, poor intracellular diffusion and the induction of resistance. It was observed that the squalenoyl-gemcitabine bioconjugate (SQgem) spontaneously self-assembled in water as nanoparticles (around 100 nm in diameter) with a hexagonal supramolecular organization.19 These SQgem nanoassemblies with remarkably high drug loadings of almost 50% (w/w) exhibited impressively greater anticancer activity than gemcitabine (gem) against both solid subcutaneously grafted tumors (panc-1, L1210 and P388) and aggressive metastatic leukemia (leukemia L1210 wt, P388 and RNK-16 LGL).20 Interestingly, it was observed that the squalenoyl-gemcitabine nanoparticles had also an impressive activity on drug resistant cancer cells.21 In the current proposal, we would like to enlarge this new and ground-breaking concept: (i) to other drug molecules and macromolecules with various physico-chemical properties (ii) by varying the nature of the polyterpene used for the drug conjugation and (iii) by giving the resulting nano-assemblies specific properties to promote more efficient targeting towards the lesion. The expected results are: (i) a knowledge of a structure/activity relationships which will allow to identify the conditions for the bioconjugates to self-organize as nanoassemblies, depending on the nature of the drug/polyterpene pair, (ii) the design of new nanomedicines with high drug loading and absence of “burst” release and (iii) a universal platform for the discovery of new nanomedicines. This cutting-edge research project is ambitious and risky but the chances of success remain reasonable thanks to the proof of concept already provided by the squalenoylation of gemcitabine. This project is clearly interdisciplinary as shown by the different stages of the research program: the synthesis of the terpenoylated bioconjugates, the design and structural characterization of the resulting nanoassemblies, the in vivo/in vitro imaging and the pharmacological evaluation of the nanomedicines. The research program is as follows: 1-Bioconjugation: Different terpenoids with increasing molecular weight (ie. sesquiterpenes like Farnesol, triterpenes like Squalene, tetraterpenes like Carotene and decaterpenes like Coenzyme Q10) will be considered for conjugation with various anticancer compounds (ie. doxorubicine, paclitaxel, cytarabine, cis-platine and siRNA oriented towards junction oncogenes) in order to increase their activity and to decrease their toxicity through selective delivery to cancer cells (see below). Terpenes will be conjugated to antimicrobial agents too, either antiviral (AZT, ddI, ribavirine) or antibiotics (penicillin, ampicillin) in order to treat intracellular infections. Finally, in order to improve the relaxivity of Gadolinium (Gd)-based contrast agents for magnetic resonance imaging, we envisage the conjugation of the Gd derivatives with different terpenes. The association in the same nanoassembly of some of the above mentioned anticancer pro-drugs with the gadolinium/polyterpenoids bioconjugates will permit the construction of “theranostics”, combining in a same nanoparticle, the double functions of (i) pharmacological activity and (ii) diagnosis/imaging possibilities. 2- Design of nanoparticles: The bioconjugates obtained will be tested for their ability to form nanoparticles in water. Their size and morphology as well as their supramolecular organization will be investigated using advanced methodologies available in different partner’s lab (ie. laser light scattering, electrophoretic mobility, transmission electron microscopy TEM, cryoTEM, X-ray diffraction by SAXS and WAXS, X-ray diffraction coupled with the microcalorimetry as well as Atomic Force Microscopy in non contact mode and in solvent). Molecular modelling will help to reveal nanoparticles supramolecular organization (hexagonal, lamellar, cubic etc.) too. The mechanism of the spontaneous self-assembling of the terpene-drug bioconjugates will also be investigated by using microfluidics methodologies (partners 7 and 3). Especially, partner 4 has developed an experimental plateform allowing the constituents to be mixed at different kinetics by stopped-flow while at the same time X-ray diffraction permits to identify the structures formed.22 The application of this advanced methodology to the different drug-polyterpene pairs will certainly highlight the mechanism and kinetic of nanoparticles formation. 3- Functionalization of nanoparticles surface: Since it is expected that these nanoassemblies will be rapidly removed from the blood stream by the reticulo-endothelial system (RES) after intravenous administration, a preferred strategy to increase their blood half-lives is their coating with poly(ethylene glycol) (PEG) chains (“PEGylation”). Therefore, polyterpenes will be conjugated with PEG and mixed at different ratios with their polyterpenes-drug counterparts before performing the nanoprecipitation. To obtain highly functionalizable nanoassemblies able to be addressed in a specific manner to target cells (ie. cancer cells or infected cells), azido-poly(ethylene glycol) will be utilized for further conjugation with specific ligands (ie. Folic acid, anisamide, RGD peptide, mannose etc.) by Huisgen 1,3-dipolar cyclo-addition (termed “click” chemistry). Alternatively, a new patented approach developed by partner 423 will use a PEG with an aryl azoture or an aryl diazonium motif able to react by photochemistry24 or covalent linkage with monoclonal antibodies (ie. anti HER-2). 4- Cell and tissue imaging: The interaction of the nanoterpenes with cells will be investigated using synchrotron radiation-based imaging techniques. Elemental mapping at the micrometer or sub-micrometer level will be performed by X-ray microfluorescence, which is the most sensitive non-destructive technique available. For this, the terpenoid based prodrugs will be associated with a metal atom to increase the contrast. Using a synchrotron source (a thousand times brighter than conventional IR sources), infrared micro-spectroscopy can achieve a spatial resolution of 3 mm, sensitive enough to detect tumor cells. The presence of terpenoid-based nanoassemblies will induce changes in the cellular metabolism and of the macromolecular folding, thus modifying the IR spectra. Magnetic Resonance Imaging (MRI) is another methodology that will be applied to investigate the cell and tissues biodistribution of the Gd containing nanoterpenes (theranostics). It is also intended to benefit from competences in FRET imaging of partner 2 to follow-up the specific cell recognition, capture and intracellular distribution of nanoterpenes. Practically, the cell tumoral markers will be labelled with quantum dots, whereas the nanoterpenes will be tagged with complexes of luminescent lanthanides.25 Other more conventional techniques will be used to investigate the pharmacokinetics and biodistribution, like scintillation counting and cell/tissue autoradiography after preparing the corresponding radiolabelled bioconjugates. The direct analysis of the terpenoid prodrugs (and of their corresponding parent molecules) will also be performed by LC/MS analysis. 5- Pharmacological activity: The in vitro pharmacological activity of the non PEGylated and PEGylated nanoassemblies with anticancer activity will be tested by measuring the inhibition of cell proliferation and cell apoptosis, comparatively to the free drug, on different cell lines (human breast, lung, ovarian, pancreatic and leukemia cancer, as well as P 388 and L1210 murine leukemia), sensitive or resistant. As far as siRNA and antisense oligonucleotides oriented towards junction oncogenes are concerned, NIH/3T3 cells stably transfected with the human EWS-Fli1 gene (Ewing sarcoma) or ret/PTC1 genes (papillary carcinoma of the thyroid) will be employed for cytotoxicity assays. For nanoassemblies with antiviral activity, the inhibition of the viral spread (ED50) will be tested, compared with the unconjugated molecules, on HIV-infected lymphocytes and macrophages; a similar approach will be done on macrophages infected with bacteria (ie. salmonella Typhymurium and listeria Monocytogenes) for the penicillin-terpene nanoparticles. The polyterpene nanoassemblies (with or without PEG) with the best in vitro anticancer activity will be tested in vivo on the corresponding experimental models. Both murine (P388, L1210, M109 etc.) and human (MCF-7, Panc-1, MiaPACA …) models, sensitive or resistant, will be used. For polyterpenoids nanoassemblies containing siRNA or oligonucleotides, experimental models of Ewing sarcoma and/or papillary carcinoma of the thyroid will be used. The efficacy will be determined by measuring the tumor growth inhibition and the long term survival. 2°/ The design of nanoparticles constructed with metal-organic-frameworks (nanoMOFs) In a very recent publication,26 partners 7 and 22 have demonstrated, as a proof of concept, that porous hybrid solids made of iron(III)- metal–organic frameworks27 may be formulated as nanocarriers with high drug loading and imaging properties. The nature of the dicarboxylic acid may tune pore size and material flexibility for better drug encapsulation. In vitro and in vivo toxicological studies carried out with various iron carboxylate nanoparticles indicated excellent biocompatibility of these nanoMOFs after unique or repeated intravenous administration. In the present project, we intended to develop the application of these new nanomaterials in two different directions: (i) the encapsulation of very hydrophilic molecules (ie. AZT-triphosphate, gemcitabine-triphosphate, cytarabinetriphosphate etc.) which failed to have acceptable payload into the usually employed polymer nanoparticles (ie.polylactic-co-glycolic, polyalkylcyanoacrylate etc.) and (ii) the encapsulation of poorly soluble compounds (in water or in organic solvents), like the anticancer drug busulfan, whom encapsulation in nanoparticles or liposomes is very challenging due to the dramatic tendency of this compound to crystallize. The surface functionalization of these drug loaded nanoMOFs will be further performed in order to control the drug release kinetic as well as the drug biodistribution. Thus, the research program will be as follows:
Busulfan is an alkylating agent widely used in combination chemotherapy regimens followed by allogeneic or autologous hematopoietic stem cell transplantation (HSCT). Hepatic veino-occlusive disease (HVOD) is the most severe and frequent busulfan high risk injury. It has been suggested that reducing busulfan liver exposure should minimize busulfan toxicity. Therefore, the development of busulfan-loaded into NanoMOFs, preferably PEGylated, which can avoid liver accumulation would be a step forward in the busulfan chemotherapy. Although partners 7 and 22 have shown the feasibility to encapsulate busulfan with exceptionally high payload into iron carboxylate nanoMOFs, the release of the alkylating agent was observed to be fast and uncontrolled (“burst release”). In this project, it is foreseen to slow down the liberation of busulfan by using iron ligands (ie. carboxylic acids) with an improved affinity for busulfan (or AZT-TP) and/or a porous architecture better adapted to those molecules (tortuosity, diffusion etc.). An alternative approach will consist in the design of a diffusion barrier at the surface of the nanoMOFs (ie.polymer overcoating) to slow down the drug release. 2- Surface decoration of nanoMOFs: NanoMOFs will be first decorated with PEG in order to avoid the liver capture of the busulfan loaded nanoparticles. Then, the redox or photochemical bioconjugation methodologies developed by partner 4 will be applied; the incorporation of azido functions will allow the easy combination of additional specific ligands (ie. folic acid, anisamide or RGD peptide for cancer targeting or mannose for the delivery of AZT-TP to HIV infected macrophages). It is also intended to functionalize the nanoMOFs surface with cyclodextrins functionalized onto one face with ligands able to recognize the biological targets. The aim is also to take advantage of the molecular dimension of the cyclodextrines to obstruct the surface of the nanoMOFs pores which should, in turn, slow down the burst release of the entrapped molecules (especially in the case of busulfan). These ligand decorated “molecular caps” will be grafted onto the core of the nanoMOFs by using reactive moieties located on the other face of the cyclodextrins and able to interact with the carboxylates or the coordinated metal sites of the nanoMOFs. 3- Pharmacological activity: For antiviral AZT-TP loaded nanoMOFs, the inhibition of the viral spread (ED50) will be tested on HIV-infected lymphocytes and macrophages. Both HIV-sensitive (HIV LAI) and resistant strains (HIV LAI 1-141 and HIV-LAI 1-144) will be used. For anticancer busulfan and gemcitabine-TP loaded nanoMOFs, the anticancer activity will be determined, as compared with the free drug, on in vitro cultivated cancer cells as well as in vivo on sensitive and resistant murine and human experimental cancers available by partner 7 (same as for nanoterpenes, see 1°/). Additionally, the efficacy and toxicity of busulfan entrapped into nanoMOFs will be tested on a specific model developed recently by Bouligand et al.28 3°/ Nanotoxicology Special attention will be paid to the safety of both nanoterpenes and nanoMOFs. In this view, both in vitro and in vivo explorations will be performed with special attention to hepatic and pulmonary tissues because they are the more exposed tissues after intravenous or pulmonary administration of nanoparticles. Other organs, like the hearth, will be investigated when they represent major toxicity target of the carried drug, as it is especially the case with doxorubicin. In vitro toxicity studies will be completed as alternative models to animal experiments. In this view, co-cultures of HepG2/J774 macrophages (liver) and calu3/alveolar macrophages (lungs) will be used to investigate nanoparticles cytotoxicity. The cell viability will be determined first on each cell type individually to identify possible membrane and mitochondrial toxicity (MTT, LDH assays). Then, the cellular toxicity will be investigated on the co-culture models after incubation once with nanoparticles or after continual exposure of subtoxic nanoparticles concentrations. In these experimental conditions, the intracellular redox status (ie.measure of reactive oxygen (ROS) and nitrogen (RNS) species, activity of superoxide dismutase, catalase, reduced and oxidized glutathion) as well as the pro-inflammatory response (IL6, IL8, TNFa etc.) will be investigated. Additionally, a toxicogenomic study will allow to identify the effect of nanoterpenes and nanoMOFs (drug loaded or not) on an important number of genes. Noteworthy, similar models of co-culture will be used to investigate the ability of nanoparticles to translocate epitheliums (pulmonary by coculture of calu3/alveolar macrophages) or endotheliums (blood brain barrier by co-culture of brain endothelial cells and astrocytes). For this part of the project, we will benefit from the “cell on chips” Microsystems developed by partner 7. Acute and subacute toxicity of nanoparticles will be tested In vivo after unique or repeated administrations in mice or rats. Again, the oxidative and inflammatory response will be documented using the above mentioned markers and the clearance ability of the reticulo-endothelial system will be checked using the charcoal assay. Special attention will be paid to the possible histological and biochemical changes of major organs (especially liver and lungs) after nanoparticles administration (either intravenously or pulmonary). Finally, specific toxicological investigations will allow to identify if a specific drug toxicity may be reduced (or increased) after administration as nanoparticles. For example, the cardiac toxicity of doxorubicin-squalene nanoparticles will be investigated, comparatively to doxorubicine free, by hearth histology and biochemistry (dosage of troponin). 4°/ Conclusion The current research project takes advantage of two novel and exciting nanomaterials (ie. nanoterpenes and nanoMOFs) to discover new and more efficient nanomedicines. Based on a multidisciplinary approach, including bioconjugate chemistry, physico-chemistry of supramolecular assemblies, drug delivery, cellular and molecular biology as well as experimental pharmacology, this proposal may led to improved treatments of severe diseases (cancer, infections), especially when they are resistant to current chemotherapy. It is expected that our project will be able to translate research concepts into drug candidates for phase I clinical trials. Nanophotonics : Nano-objects for energy control (leader : Jean-Jacques Greffet, LCFIO/IOGS)
State of the art Nanophotonics is a new topic that develops very fast in an extremely competitive worldwide community. It has been selected as one of the falgship research because i) it has a large innovation/intellectual property potential, spanning from the domain of information and communication to the emerging domains of bio-medical imaging and diagnosis, sensors and renewable energies, ii) the Nano-Saclay community is one of the largest academic community worldwide, covering all aspects of the topic from the most fundamental ones (Quantum Information Processing and Computing, or QIPC) to mid-term and even short term applications (imaging and object manipulation at the molecular level, photovoltaics, telecom devices, …), and from semiconductor nanophotonics to biophotonics, iii) it offers a strong potential for a multidisciplinary approach. The nanophotonics project results from a collective work of representatives of 35 research groups in nanophotonics, nanofabrication, nanomaterials and nanochemistry. The first task was to identify strengths of the nanophotonics community in Saclay. The second task was to identify a small number of key challenges in nanophotonics where the Saclay community can make a significant contribution through a collaborative scheme. In particular, the role of the Nano-Saclay excellence laboratory is seen as a means to promote a collaborative approach gathering nanochemistry, nanofabrication and nanophotonics. The project has strong links with the TEMPOS (O. Stephan) and the STRAS (G. Dujardin) equipex project. The key challenges are shortly described in the following text. They are organized in three topics. For each topic, a task leader was chosen. He will be in charge of organizing the collaborative work of the different groups participating in each task. A bureau composed of the project leader and the three task leaders will be in charge of assigning ressources. The NanoSaclay project has established a research program focussed on several challenges that have been identified: i) Generating, studying and using extremely weak optical beams, down to the single photon manipulation. A new paradigm that we call «few photon optics». This topic is both at the center of the fundamental questions on light-matter interaction at the nanoscale and of key importance for the development of new information processing technologies. ii) Plasmonics: quantum plasmonic optics, (electrical) plasmon amplification, resonators. Despite decades of research on plasmonics, plasmon quantum optics and amplification of plasmons are still largely open questions. Beyond fundamental issues, plasmons are very promising for ultrasensitive detection and photovoltaics. iii) Optical manipulation of functionalized nano-objects, down to the single molecule level. Whereas optical tweezers are ubiquitous in manipulating micro-objects, no general technique exists for nanoobjects. This is a key challenge. To deal with these challenges, the NanoSaclay Excellence lab has selected a task force of 54 highly qualified researchers. They have authored 76 papers quoted more than 100 times. The list includes 14 researchers with impact factor above 20 (including 7 above 30). Since 2006, they have made several breakthroughs in the field with 21 papers published in Science or the Nature publishing group, 37 papers in Phys.Rev.Lett. and 13 in Nanoletters. A key feature of the task force is the blend of physicists, experts in nanofabrication and chemists. Another key feature is the strong interaction of teaching and innovation in the project. The members of the task force have filed 30 patents since 2006 and cofounded 3 start-ups. Researchers of three companies (Thales, Genewaves, 3-5 lab) are involved in the project.
One of the most spectacular consequences of reducing the size of the playground where photons and electrons/phonons/excitons interact is the potential for having interactions with extremly low power close to the single photon level. Few-photon optics is becoming a new paradigm. Sub-wavelength optical resonators using advanced processing of photonic crystal structures are intensively studied worldwide with perspectives such as optical functions with extremely low power, giant enhancement of optical non-linearities, integrated optics using a single processing technology. Non-linear effects with only two photons are within reach. Spectacular progress in synthesis of nanometric-size emitters (bottom-up approach) and nanoscale processing (top-down approach) are opening fascinating perspectives for the practical use of few photon optics. There is intense competition in new core-shell II-VI based structures and new color centers in diamond that offer promising solutions to the «blinking» of colloidal nanocrystals that has hampered the developpement of in-vivo imaging with functionalized luminescent particles. Nanodiamond is a remarquable example of a system where both QIPC applications at room temperature and bio-compatible imaging properties have been demonstrated. Another example of bottom-up approach is the emerging field of nanowires that form a new paradigm in semiconductor epitaxy where 3D structuration with extraordinary versatility can be obtained directly from the crystal growth process. As a single example of the combination of approaches, LPN has recently demonstrated a solid state source of entangled photon pairs29 that was hardly conceivable two year ago. These advances are feeding major forthcoming progress both in the fundamental field of QIPC and in practical applications in classical information processing, photovoltaics, as well as in multidisciplinary applications in sensors, biology and medicine. Plasmonics With the advent of near-field microscopy and the development of nanofabrication techniques, plasmonics has become one of the most active topics in nanophotonics. It offers new avenues to control light-matter interaction at a nanometer scale. Despite a tremendous amount of work reported in the last ten years, several challenges are still unresolved. One of them is surface plasmons quantum optics. If the quantum nature of surface plasmons is well-known since the early days of surface plasmons, surface plasmon quantum optics is still in its infancy despite a few demonstrations of conversions of single photons in single plasmons.30 The first experimental demonstration of surface plasmon antibunching has been reported on nanowires.31 No genuine quantum optics phenomenon has been demonstrated on surfaces. A second challenge is the electrical generation/amplification of surface plasmons. While gain for surface plasmons and lasing has been demonstrated very recently,32-35 the electrical generation and amplification of surface plasmons is still a challenge. Surface plasmon lasing with electrical gain is in particular a major issue. The interplay between electrical gain in metallic structures and losses in metamaterials is of particular practical importance. Finally, a remarkable playground for plasmonics is resonators/antennas to enhance light-matter interaction. This has potential applications for solar energy production36 and biosensing37 where the challenge is to reduce as much as possible the amount of absorbing material. This particular topic has a lot of potential for innovation. Nano-object optical manipulation Trapping, moving or actuating nanoscale systems is a key technology for both fundamental and applied research. Steering and monitoring matter at the nanoscale requires the knowledge of physicists, chemists and biologists. Applications span from the mainstream of manufacturing to diagnostics, therapeutics, or trace-sensitive sensors, as well as ultimate information technologies. This is achieved currently by optical tweezers. They constitute an indispensable tool in biology, physical chemistry and soft-matter physics.38 Yet, they are limited to objects with a size on the order of hundreds of nanometers. A key challenge is to develop a new generation of optical traps in order to be able to manipulate at nanoscale individual objects with sizes down to the single molecule. Progress towards the optical manipulation of ever smaller objects requires both new concepts of optical manipulation and the corresponding enabling technologies. Yet, several recent scientific advances open highly promising opportunities in two directions. Firstly, the large gradients in intensity of light associated with plasmonic modes have been exploited for nano-manipulation. Demonstrations are based on specific designs of tweezers substrates, or of the target object itself.43 Even higher confinements have been predicted, e.g. through the nonlinear response of molecular solitons. Secondly, highly efficient molecular photo-switches have been shown to be able to act as optically-fueled molecular-scale motors. Associated with liquid crystals, they are able to rotate large objects.44 Similarly, functionalization with photo-isomerizing azo molecular moieties has been demonstrated to be at the origin of photoinduced mass transport. Such systems are able to convert light energy into mechanical work much more efficiently than the radiation pressure, at play in conventional optical tweezers, does. Applying the above principles independently, optical manipulations of objects with sizes down to a few tens of nanometers have been demonstrated. However, the configurations used require very specific objects and immediate environment, which prevents applications as generic nano-imaging instruments or nano-manipulating tools. Objectives of the project Few photon optics (leader: Paul Voisin, Board: JC Harmand, JP Hermier, A. Loiseau, S. Sauvage) Partners : 2, 3, 6, 11,19, 20, 22 Three challenges have been selected, where important progress can be anticipated during the next 4 years, and where coordination of different team activities will result in strong added value. Nanosources Deterministic integration of nano-emitters into resonant microcavities is an essential step for Quantum Information Processing and Computing (QIPC), and strong efforts will be devoted in this direction. We will explore synthesis and characterization of innovative nano-emitters, like new color centers in nanodiamond and new, non-blinking core-shell colloidal nanocrystals, and semiconductor carbone nanotubes with 2-year perspectives in room temperature operation of single photon sources and bio-imaging. Specifically, the in-situ lithography technique recently demonstrated by LPN will be further developed both for self-assembled InAs-GaAs quantum dots and for other quantum emitters. New cavity design, and new coupling schemes will be explored, such as photonic Tamm states and plasmonic nano-antennas, with 2-year and 4-year objectives in QIPC. Nanowire and nanotube project conjugates a massive effort on crystal growth and characterization of these new objects (in connection with the equipex proposal « tempos »), and the developement of nanowire/naotube based photonic devices. 2-year objectives include the demonstration of a single photon emitter formed by a quantum dot inserted in a nanowire, with size and morphology optimized for efficient light extraction, the growth of III-V nanowires on Si, with coupling of a nanowire array to a SOI planar waveguide, the extraction by chemical sorting techniques of pure carbon nanotubes with controlled chirality leading to tunable single photon sources in the near infrared. Our 4-year objectives are the demonstration of optical functions with III-V nanowires on Si and of functionnalized chirality-controlled nanotubes, for use in solar cells and biological sensors and of single photon sources at telecom wavelengths. Ultimate non-linearities Among the huge number of subtopics in this wide field, we shall concentrate on cavity-enhanced light-matter interactions allowing non-linearities with extremely low excitations, from the femto-joule range down to the ultimate quantum limit of two-photon non-linearity. Again, the project admixes long term QIPC perspectives, fundamental studies such as exciton-photon non-linearities leading to polariton Bose condensates and new effects and functionalities using them, and shorter term device oriented research including an ultracompact Si Raman laser and ultrafast photonic crystal based logical gates. Another high potential exploratory line concerns localized electron-phonon interactions in the linear (polaron) and non-linear regimes (optically driven Sound amplification or SASER). Two-year demonstrators include < 5 photon bistability, superfluid propagation and interferometry of polariton condensates, as well as Si (low noise Raman laser, bio-sensors) or III-V-based (ultra fast optical gates) photonic crystal devices. 4 year objectives include advanced quantum optics experiments combining single photon sources and 2-photon gates, electrically driven polariton circuits, advanced ultrafast integrated optics circuit, and demonstration of the THz quantum dot SASER effect. Plasmonics (Leader: R Colombelli. Board : P. Lalanne, JJ Greffet, O. Stephan) Partners : 2, 3, 9, 14, 19, 24. The interest recently devoted to surface-plasmons is motivated by their ability to confine electromagnetic radiation at visible and near-infrared frequencies over extremely sub-wavelength mode volumes. The enhanced light-matter interaction yields applications ranging from (bio)-detection to energy-harvesting. The rapid expansion experienced by this field is also due to the availability of a variety of crucial tools: nanofabrication, advanced micro- and nano-optical characterizations, and also extremely predictive methods for numerical simulations. In this part of the project, leaders in the all the aforementioned fields will gather the forces to promote a major step-forward, by (i) elucidating fundamental problems in plasmonics, and (ii) exploiting plasmonic resonances for real-world applications like components and systems for bio-photonics, and photovoltaic devices.
The importance of this action cannot be underestimated. To cite an example, transparent metamaterials could become available. In turn, this will enable the development of perfect lenses. These long-sought optical components – also known as superlenses – allow one to beat the diffraction limit of standard optical devices/components. Plasmonic resonators: Photovoltaics is a first promising application, since plasmonics allows one to boost the absorption of photovoltaic devices. This is particular appealing given the current trend towards development of low-cost, thin-film solar cells. In this context, strong absorption at plasmonic resonant wavelengths in 2 years, and a complete photovoltaic plasmonic cell in 4 years are realistic objectives. A second, promising perspective is the development of materials, components and systems for bio-detection. Surface-amplified mechanisms are already used for detectivity-enhancement issues. What nanotechnology can add in this case is the selectivity: artificially made plasmonic nanostructures can target a specific molecule, for instance. Multipolar plasmonic nano-antenna arrays capable of detecting less than 10 targets will be developed within 2 years, and detection of one target only will be attained by year 4. Nano-object optical manipulation (leader: F Charra. Board : G. Dujardin, R. Kuszelewicz, K. Nakatani) partners : 2, 4, 5, 8, 11, 15, 16. The goal of our project is the noninvasive optical manipulation of nano-objects with ultimate sizes, down to the single molecule. To this aim, we propose to combine high optical confinement techniques with molecular-level mastering of the conversion of light energy into mechanical work, following an integrated multi-disciplinary approach involving optical physicists and surface organic chemists. More specifically, the consortium gathers internationally recognized specialists of the design and fabrication of photo-switchable molecules (K. Nakatani) nano-objects (A. Bleuzen) and functionalized surfaces (S. Palacin) or nanoparticles (C. Reynaud), of the control of nano-object switching, from single molecules (G. Dujardin) and nano-objects (A. Debarre) to mass-transport (J. Peretti), as well as of the optical field localization through nano-structures (F. Charra) or non-linear propagation (R. Kuszelewicz). A special emphasis is put on the know-how in local probe techniques and optical spectroscopy of single nano-systems. Two strategies will be employed.
An important consequence of the noninvasive 3D manipulation of nano-objects is the possibility to extend scanning-probe microscopy techniques from surfaces to bulk media. To this aim, specific and highly sensitive optical means for monitoring probe environment must be implemented. A demonstrator of such an unprecedented instrument will be realized as part of this project. Intermediate proof-of-concept demonstrations will be carried out after two years for 3D imaging using optical tweezers and for 1D and 2D-confined optically-induced motion of nanoparticles and single-molecules.
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