ERC FUNDED PROJECTS

Targeted drug delivery across the blood brain barrier (BBB) to the central nervous system is a large challenge for the treatment of neurological disorders. This 4 year ERC program is aimed towards the evaluating the BBB penetration capacity and toxicological potential of novel carbon nanotube (CNT) carriers using an integrated multidisciplinary approach. State-of-art characterisation techniques developed by the PI will be applied and further developed to detect the interaction of carbon nanotubes with in vitro BBB model and neuronal cells. Specific aims: 1. Identify the mechanisms of translocation of CNT across the endothelial cells which comprise the BBB, as well as uptake by neuronal cells in vitro. 2. To investigate the effect of length, diameter and surface charge of CNTs on the BBB and neuronal cells penetration capacity in vitro. 3. To investigate the toxicological profile of CNT on the BBB and the various neuronal cell types (immortalised and primary neuronal cultures). 4. Develop protocols to assess whether the CNTs degrade inside the cell. The ERC Grant will consolidate the new Research Group in nanomaterials-cell interfaces, and allow them to perform stimulating investigator-initiated frontier research in nanotoxicology and nanomedicine. To this end, a multi-disciplinary laboratory will be realized within the framework of this 4-year the ERC Programme. This will permit the group around the PI, to expand activities, push limits, create new boundaries, and develop new protocols for studying nanoparticle-cell interactions in close collaboration with ICL s Department of medicine and chemistry. Within the proposed program there is an underlying ambition both to gain a fundamental understanding for which parameters of CNTs determine their penetration capacity through the BBB and also to assess their toxicological potential at the BBB two highlighted themes by the ERC.

1 229 998 €

Start date: 2011-02-01, End date: 2017-01-31

A signature trait of living systems is their ability to dynamically adjust to features of their environments, adapting to stay alive, and evolving to take better advantage of the resources in their environments. This proposed research aims to synthesise new chemical systems that are capable of adaptation and evolution, with the achievement of specified functions being used as the benchmarks by which we may be judged to have succeeded in setting the direction for our systems evolution. Two parallel lines of inquiry will be followed. First, we will build upon results that we have recently published in Science[1] to create a series of new molecular capsules that are capable of dynamically adapting to different guest molecules. These capsules will serve as sensors and as enzyme-like catalysts through the use of transition-state-analogue guests. Second, we will prepare new metal-containing conjugated polymers through self-assembly, which will be capable of dynamically exchanging building blocks in solution. These polymers will have potential applications as electrically-conductive materials, with functional properties that may be tuned and optimised by the application of evolutionary pressures. The success of these studies will thus create novel materials with uses as self-assembled sensors, catalysts, and electrical conductors. We will also shed light upon the question of how chemical systems may be induced to evolve under selective pressure. These studies thus have long-term bearing upon the questions of how living systems evolved from pre-biological mixtures of molecules. [1] P. Mal, B. Breiner, K. Rissanen, J.R. Nitschke, Science 2009, 324, 1697-1699.

1 357 006 €

Start date: 2011-01-01, End date: 2016-12-31

The main vision of the project ENERCAPSULE is the development of nanoencapsulation technologies based on switchable nanoscale barriers for novel generation of controlled energy storage and delivery systems. These systems will be based on the “smart” nanocontainers (size below 200 nm) loaded with the energy-enriched active components: materials for thermal energy (both latent and based on chemical reactions) storage and substances for bioenergy (ATP or its components) storage for synthetic biology platforms. First novelty of the proposed project is the protection of the nanoscaled energy-enriched materials against environment during storage and controlled release of the encapsulated energy on demand only using both inherent properties of nanocontainer shell or biomimetic nanovalves introduced as shell components. Another main objective of the project is to study the structure and surface-to-volume properties of the energy enriched materials dispersed and encapsulated on nanoscale. The questions of stability of energy nanomaterials, influence of the nanocontainer shell on their energy capacity, homogeneity and operation lifetime will be investigated. Polymer organic nanocapsules with hollow interior and mesoporous carbon nanoparticles are chosen in the project as main types of the nanocontainer scaffolds for energy-enriched materials due to their high loading capacity and potential to design their shells to attain them controlled permeability properties. At the end of the project, developed novel energy storage and delivery systems will be combined within one network having several mechanisms for release and uptake of energy, which can be activated depending on type and intensity of the external impact (demand). The potential applications of such multienergy storage systems will be tested by industrial companies supporting the project.

2 004 500 €

Start date: 2015-09-01, End date: 2020-08-31

Organic molecules of all shapes and sizes are required for a multitude of applications in numerous settings, such as in the biomedical, pharmaceutical, and agrochemical industries (among others). To meet this demand, organic synthesis is faced with the challenge of converting simple, readily available chemical building blocks into more complex structures in as rapid, efficient, and cost-effective a manner as possible. As such, increasing the efficiency of organic synthesis provides enormous benefits to society, quality of life, and a sustainable future. In this proposal, we outline a program aimed at the design, development, and application of new asymmetric transition metal-catalyzed reactions, where a chiral catalyst will control which particular enantiomer of a chiral product is formed. This feature is absolutely vital, since the action of chiral functional molecules within a chiral environment (such as in biological systems) is critically dependent upon their three-dimensional shape, and hence their enantiomeric composition. Several sub-project areas (each based around transition metal ions for which our group has had prior expertise) are presented, which target compounds from simpler chemical building blocks (copper- and rhodium-catalyzed reactions) to those of higher complexity (nickel-catalyzed domino reactions). During the course of this research, we anticipate that a host of useful discoveries will be made that will positively impact the discipline of organic synthesis for the ultimate benefit of society.

1 498 892 €

Start date: 2011-01-01, End date: 2015-12-31

The creation of new molecular entities and subsequent exploitation of their properties is central to a broad spectrum of research disciplines from medicine to materials but progress has been limited by the difficulties associated with chemical synthesis. We are now proposing a fundamentally new strategy, which has the potential to revolutionise how we conduct complex organic synthesis. The basic C–C bond-forming step involves the reaction of a lithiated carbamate with a boronic ester to give a homologated boronic ester with complete stereocontrol. Furthermore, the reaction shows >98% efficiency in most cases and can be conducted iteratively and in one pot (up to 9 iterations has been demonstrated with full stereocontrol). We will now extend this methodology to more functionalised carbamates as this will enable the rapid synthesis of polypropionates, which are amongst the most important classes of biologically active molecules. The robust methodology is now ripe for transfer to the solid phase as this will enable the preparation of libraries of these molecules. Through applying our assembly-line-synthesis methodology to complex molecules with diverse structures, we will demonstrate its scope, robustness, and full potential. The methodology enables stereochemistry to be ‘dialled in’ to a carbon chain, which in turn controls the conformation and we will exploit this feature in the shape-selective synthesis of molecules. We will explore how the sense of helical chirality of these molecules can be switched (M to P) just with light. We will target helical molecules with specific groups at specific places for optimum binding to disrupt protein–protein interactions involved in cancer. Finally, our methodology provides ready access to a family of building blocks that represent common repeat units found in polyketides. By combining these building blocks iteratively using lithiation-borylation, we should be able to rapidly and reliably prepare complex natural products.

2 436 379 €

Start date: 2015-10-01, End date: 2020-09-30

Metal-organic frameworks (MOFs) constitute one of the most exciting developments in recent nanoporous material science. Synthesised in a self-assembly process from metal corners and organic linkers, a near infinite number of materials can be created by combining different building blocks allowing to fine tune host guest interactions. MOFs are therefore considered promising materials for many applications such as gas separation, drug delivery or sensors for which MOFs in form of nanoparticles, composite materials or thin films are required. For MOFs to realise their potential and to become more than just promising materials, a degree of predictability in the synthesis and the properties of the resulting material is paramount and the full multiscale pathway from molecular assembly to crystal growth and thin film formation needs to be better understood. Molecular simulation has greatly contributed to developing adsorption applications of MOFs and now works hand-in-hand with experimental methods to characterise MOFs, predict their performance and study molecular level phenomena. In contrast, hardly any simulation studies exist about the formation of MOFs, their crystal growth or the formation of thin films. Yet such studies are essential for understanding the fundamentals which will ultimately lead to a better control of the material properties. Building on my expertise in molecular modelling including the development of methods to model the synthesis of porous solids, we will develop new methods to study: 1. the self-assembly process of MOFs under synthesis conditions 2. the formation of nanoparticles 3. the integration of MOF nanoparticles into composite materials and the self-assembly into extended structures 4. the layer-by-layer growth of thin films At the end of the project we will have transformed our understanding of how MOFs form at a variety of length scales and opened up new research directions for the targeted synthesis of MOFs fit for applications.

1 738 715 €

Start date: 2015-08-01, End date: 2020-07-31

Synthesis is a fundamental area of science that is crucial to advances in medicine and materials - fields that directly impact modern society. The increasing challenges that our society presents has raised the demands on synthesis to provide new molecules that can perturb biological function or provide a new physical property. This fellowship aims to provide solutions to these problems by developing pioneering synthesis blueprints for how chemists can make any molecule in an efficient, rapid and green fashion. In particular, direct benefits of this research will be realized in the treatment of disease. The bond forming processes that underline our ability to make molecules, large or small, depends on the manipulation of pre-functionalized molecules (compounds that need to be prepared through additional synthetic steps). However, the most common type of chemical bond in almost all organic molecules is the C H bond. Usually, all but a few of these C H bonds are considered as inert and only useful in synthesis if they are in the vicinity of a one of these activating functional groups. To a synthetic chemist, permitting the use of any C H bond as a potential functional group would be like giving them a key to a new world Discovery of new chemical reactivity would lead to new reactions; comprised into a new tool kit for synthetic chemists, this would provide the basis for a molecule-building blueprint that would challenge synthetic dogma. Furthermore, using the traditionally inert C H bond as a versatile functional group would save synthesis time, make synthesis greener , and hence more efficient and cost effective. Therefore, to be able to introduce a general blueprint for chemical synthesis based using any C H bond as a versatile functional group would be a truly paradigm shifting advance, and could have enormous impact on many of the scientific challenges that affect modern society.

1 499 983 €

Start date: 2011-01-01, End date: 2016-12-31

We propose to undertake an ambitious 5 year interdisciplinary programme that introduces a fundamentally new paradigm in protein-based nanomaterials research. The new approach involves two main project themes based respectively on fundamental studies on the structure, function and properties of molten protein polymer surfactant nanoconstructs, and the development of these novel nanomaterials as smart fluids, biotechnological devices and health care products. This proposal represents a new and adventurous area of work for the PI, and will allow unprecedented access to a novel class of nanomaterials with controllable architectures, unique physical properties and inherent biological functionality. In so doing, the work will open up promising new avenues of bionanomaterials research and offer significant advantages over current methods for producing protein-based nanomaterials at extremely high concentration and dosage. In general we expect the research programme to pioneer new frontiers in fundamental research and generate significant economic and societal impact as nanomaterials become increasingly integrated into medical and technological products, and new commercial markets based on nanoscience are discovered.

2 168 862 €

Start date: 2011-03-01, End date: 2016-02-29

We aim to offer to science a molecular scale mechanism for communication and control. Using stereochemical information and conformational control as the mechanism by which that information is transmitted and processed, we take inspiration from the phenomenon of allostery in biology, and will put to dynamic use a set of conformationally controlled foldamer structures. We will use these structures to convey information over multi-nanometre distances, allowing control of chemical function from a remote site. By embedding the foldamers into membranes, we will control chemistry (eg catalytic activity) within an artificial vesicle by communicating information through the chemically impermeable phospholipid bilayer. To achieve our aim we will synthesise oligomeric and polymeric compounds with well-defined helical conformations, and use a stereochemical influence located at one terminus to induce a conformational preference (for the left or the right handed form of the helix) which is relayed to a site many nanometres distant. Precedent suggests that by employing polymeric structures we will achieve control even over micrometre scales. Simple but powerful new techniques will quantify the remote (on a molecular scale) transmission of information by NMR, circular dichroism spectrophotometry and/or fluorescence. The result of the information relay will be a detectable change in chemical reactivity or binding properties and one aim will be to vastly increase, by orders of magnitude, the distance over which remote stereochemical control is possible (from the current 2.5 nm to the order of >100 nm). The feature which distinguishes biology from chemistry is information, and in particular the ability to encode and process information using molecular interactions. Our project will take a step towards the development of designed chemical structures which can mimic, using far simpler molecules, the function of biological communication systems.

2 426 106 €

Start date: 2011-04-01, End date: 2016-03-31

The development of new innovative approaches for personalised healthcare, and the recognition and sensing of environmentally important pollutants resulting from anthropogenic activities, are extremely important areas in which chemical understanding can contribute enormously to the improved well-being of humanity. In particular, the recognition of anions in aqueous media remains a significant challenge. This project will exploit cation-anion interactions augmented by supramolecular chemistry in the preparation of novel heteroditopic receptor molecules for lanthanide cation- anion ion pair recognition. These have the potential to revolutionise magnetic resonance imaging for personalised healthcare, and will provide interlocked host systems capable of sensing and analyte induced molecular motion. Particular emphasis will be given to the construction of heteroditopic macrocyclic and interlocked host systems designed to recognise lanthanide cation-fluoride anion ion pairs. The stimulus for recognising the fluoride anion stems from its duplicitous nature, where for example high levels in drinking water is causing dental and skeletal fluorosis. In stark contrast, importantly for personalised healthcare, fluoride anion recognition offers the potential development of novel 19F MRI and 18-fluoride PET imaging agents. The programme of work in this proposal centres around three closely integrated and synergistic strands. The common theme is to exploit lanthanide- fluoride ion pair recognition in multimodal imaging (Strand 1), to construct interlocked host structures for fluoride recognition, sensing and molecular machine-like induced switchable behaviour (Strand 2), and to assemble interlocked host systems onto transducing surfaces for analyte induced molecular switching (Strand 3).

2 488 849 €

Start date: 2011-03-01, End date: 2017-02-28