SNAL · Smart Nano-objects for Alteration of Lipid-bilayers

Smart Nano-objects for Alteration of Lipid-bilayers

The EU-funded 7th Framework Programme (FP7) Initial Training Network (ITN) SNAL has the main objective to train a new cohort of researchers with systemic thinking equipped with generic skills in combining experimental studies and computer simulations to prepare them for fruitful careers in academia and industry. One challenge for the project is the design and synthesis of novel biomaterials able to modify membrane properties. Many proteins, synthetic polymers and nanoparticles interact with cells and the ability to influence this association is key to the design of novel medical treatments. The aim of SNAL network (https://itn-snal.net) is to understand the interactions of lipid membranes with nano-objects including functional biomimetic polymers, polymeric micelles, carbon nanotubes and polymer therapeutic complexes/conjugates to enable the intelligent design of novel materials with improved bilayer modifying properties. The multidisciplinary project combines computer simulation, chemical synthesis, clinical and industrial expertise, physical and biological experiments to design and test completely new synthetic nano-objects that mimic the essential properties of membrane-interacting biopolymers. The full cycle of the design process, from theoretical concepts towards chemical synthesis and experimental to in-vitro validation. Numerous network events https://itn-snal.net/network-events/, regular meetings on biomaterials and lipid membranes http://meeting.softmat.net/ and a summer school in Sicily, http://school.itn-snal.net/ permitted the sharing of knowledge between the partners and disseminate the scientific results of the network to the extra-network community. Work package 1 is devoted to the theory and simulation of lipid bilayer systems in contact with nanoparticles, nanorods, or rough hydrophobic surfaces. Complementary simulation models and numerical approaches are used and further developed to obtain detailed molecular information and to test assumption of simplified theoretical models. At the Imperial College in London, atomistic simulations are applied to specific skin-like lipid bilayers, At the Leibniz Institute of Polymer Research in Dresden, coarse grained models are used to study the generic physics of nanoparticle- polymer interactions and corresponding changes in lipid bilayers. At the Universitat Rovira i Virgili in Tarragona, self-consistent field models are applied to study the formation of pores in lipid bilayers and generic elastic models are developed for red blood cells in order to study the interaction with rough hydrophobic surfaces. Work package 2 is devoted to development of a biomimetic polymers for delivery of payloads into cells. Novel pH-responsive, lysine-based, hyperbranched polymers have been synthesized to mimic the transport pathway of endosomolytic cell-penetrating peptides into cells and allow for endosomal escape at the same time. The critical details of in-vitro responses of nano-objects are highly sensitive to their hydrophilic / hydrophobic balance, charge, and morphology. Within this package, it has been demonstrated that even hydrophilic apatite nanoparticles serve as biocompatible delivery vectors that, for instance, will help Biopharma to load erythrocytes with trehalose in order to enhance the preservation of freeze-dried blood. In Dresden it was demonstrated by coarse-grained simulations that flexible polymers with a balanced ratio of hydrophilic / hydrophobic units mimic pore-forming peptides by reducing the line tension of a pore. Work package 3 devoted to model lipid bilayers and focuses on the investigation of the behavior of pH-responsive nanoparticles in model lipid systems, by applying a combination of complementary experimental techniques. In particular, to study the influence of pH variation on the membrane-disruptive behavior of biomimetic polymers and the effect of incorporation of polystyrene in the inner region of the lipid bilayer. Another direction was to study flat geometry of lipid mono- and bi-layers allows for the use of cutting edge techniques, e.g. neutron reflectivity, dual polarisation interferometry, ellipsometry, etc. in order to identify the intrinsic features of the interactions between nano-objects and the lipid systems under consideration. The work started with establishing the methodology for producing robust supported mono- and bi-layers via Langmuir trough. Experimental information provided feedback for system improvement of nano-objects interacting with model membranes (supported bilayers and vesicles). Work package 4 and 5 are devoted to study interaction of nano-objects with living cells and tissues and toxicity of nano-objects. In particular, this work aims at the study of cytotoxicity of nano-objects in human cells models and the behavior of these nano-structured systems when in contact with cells. The results are validated by comparing the system’s response using cell lines and primary cultures. Work package 6 is devoted to technology transfer. Two companies, Unilever and Biopharma were in charge of the business impact of the project. Individual partners have communicated their own ideas for which they are pursuing support on a project by project basis. There were several ideas which scored highly and resulted in further technology transfer possibilities. Unilever expects and foresees that exploitation will be mostly in this academic area. The scientific content of the modelling studies will no doubt resonate with the considerable body of information already available on skin within Unilever and the most likely outcome is that these learnings will be added to a wider portfolio of activities with other digital partners. Biopharma is applying for a patent to cover some of the specific aspects of the work on cryopreservation of cells using nanoparticles studied within SNAL project, that will enhance its current worldwide patent on the freeze-drying and rehydration of biological materials. This is an opportunity to further study structure function relationships in membrane-active agents using both modelling and experimentation.

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