Understanding the interaction of nano-sized synthetic materials with biological membranes
Location: CECAM-HQ-EPFL, Lausanne, Switzerland
Organisers
-- WORKSHOP FULL! --
The last two decades have been characterized by an extraordinary growth in the production and commercialization of nano-sized materials. Safety is a major concern when new materials are produced, and especially so for nanomaterials, since their properties are very different from the properties of bulk materials with the same chemical composition, and are difficult to predict. At the same time, nanometer size materials offer unprecedented opportunities in many fields of technology, including pharmaceutical and medical technology. The increasing use of synthetic nanoparticles, and biological counterparts such as nucleic acid and protein assemblies, makes it important to understand how such particles interact with biological matter.
Biological membranes are the first barrier encountered by any particle entering an organism. The interaction of nanoparticles with biological membranes is therefore of paramount importance to understand the molecular basis of biological effects. For example, carbon nanoparticles, such as fullerenes, carbon nanotubes, or amorphous carbon NPs are known to enter cell and lung membranes, but their toxicity on living cells is not well understood. Metal, metal oxide and polymeric nanoparticles may also enter biological membranes, with unknown consequences. Finally, micelles and vesicles made from synthetic amphiphilic copolymers are increasingly used as drug or gene nanocarriers because of their superior mechanical properties and long circulation times. In all these cases, nanoparticle biological activity is mediated by biological membranes.
We have two aims with this proposed workshop. On the one hand, we propose to bring together experts in modelling biological membranes and synthetic materials, to discuss the most effective strategies to simulate their interaction. The workshop will be a unique opportunity for dialogue between two communities that have an interdisciplinary research interest, at the boundary between material science and biophysics. On the other hand, we also aim to involve experimental scientists interested in the characterization of nanoparticle-membrane interactions and in the design of synthetic materials for technological application. The workshop will therefore promote fruitful collaboration between theoreticians and experimentalists.
Synthetic materials – biological membrane interaction: recent developments
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The recent development of methods to produce and manipulate materials at the nanometer scale opens new opportunities for applications in many fields of technology. It also raises concern about possible toxic effects of nano-sized materials, since properties of nanoparticles are very different from those of the same materials in bulk form [1]. The interaction of synthetic materials with living organisms is generally mediated by biological membranes, which are the first barrier encountered by substances entering cells. Experimental, theoretical and simulation studies on the interaction between membranes and different kinds of synthetic nano-sized materials have recently started to appear in the literature.
Carbon NPs – membranes
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Both computer simulations and experiments have shown that model membranes are able to accommodate large concentrations of hydrophobic solutes, without undergoing any mechanical damage (see [2] and [3] for the case of fullerene). Interesting results are instead emerging concerning the effect of hydrophobic solutes on various membrane properties, such as structural, dynamic and elastic properties, as well as the lateral organization of heterogeneous membranes. Alterations of membrane properties can have important effects on cellular functions.
Polymers – membranes
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Degradation of every-day use plastics results in the formation of micrometer and nanometer-sized polymer particles. Concern has recently been raised on the effects of those plastic particles on living organisms [4], but there is very limited understanding of the interaction of biological membranes with synthetic polymers. Small polymer particles are also produced for diagnostics and pharmaceutical applications. Polymer amphiphiles, such as Pluronics, are designed to interact with and target specific organs of the human body. Their interaction with membranes is a key step in the delivery of drugs and other substances, and is the object of recent theoretical and experimental investigation [5].
Metal and metal-oxide particles – membranes
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Metal and metal oxide NPs are promising tools for therapeutics and diagnostics (the so-called theranostics) [6]. For example, a vast literature accounts for the qualities of iron oxide NPs, which have been used for in vitro diagnostics for nearly half a century. Research is nowadays aiming at identify other biocompatible magnetic metal oxide materials, and at the same time the challenge is to control size, shape, stability and dispersibility of such NPs in the desired solvents. Metal oxide NPs (FeO, TiO, CuO) are also found in environment, and have been reported to cross biological membranes and accumulate in the cell. TiO2 NPs were found to be toxic, and the toxicity mechanism involved the destabilization of cell membranes [7].
Computational techniques
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Biological processes occupy a wide range of length and time scales, and involve interactions ranging from molecular binding at the nanometer scale to diffusion and transport across micron length scales. Direct observation of the dynamics of nanoparticle-membrane behaviour is experimentally difficult, and has limitations in the length and time scales accessible. Computer simulations can describe the forces acting between nanoparticles and membranes and predict their behaviour under a wide range of conditions. Atomistic Molecular Dynamics is most accurate for studying direct inter-molecular interactions, but is limited to small regions of space (a few tens of nanometers) and time scales up to microseconds [8]. To explore the dynamics of larger portions of matter for longer times, some simplification is required. Coarse-grained Molecular Dynamics relies on grouping atoms in effective interaction sites, reducing the number of degrees of freedom in the system [9]. Dissipative Particle Dynamics is a coarse-grained simulation technique that is mathematically similar to Molecular Dynamics but operates on length scales from 1 - 1000 nm, and time scales up to milliseconds [10]. In this regime entropic forces play a crucial role in stabilising non-equilibrium structures. For example, membrane fluctuations of a cell can drive adsorbed particles to aggregate in distinct patterns under appropriate conditions [11]. Some of these patterns are biologically important, as when shiga toxin particles cooperatively drive invagination of a cell [12]. Brownian Dynamics is another coarse-grained technique that can capture dynamics of particles on these length scales, and enables structural rearrangements that are slow on molecular time scales to be followed in simulations. Monte Carlo simulations of triangulated surfaces are able to simulate complete vesicles and reveal their shape transitions, and response to surface fields such as the membrane curvature coupling to an in-plane nematic field [13], or the adsorption of curvature-inducing nanoparticles to the membrane. All of these techniques provide a window onto the dynamics of membranes that cannot be seen with atomistic Molecular Dynamics, yet are too small and fast to be observed in optical microscopy. They provide therefore a valuable source of insight into molecular rearrangements that take place during cellular processes such as invagination [12], tubulation [13], nanoparticle aggregation on vesicles [12,14], etc.
Experimental techniques
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Interactions of nano-sized materials with living organisms have been studied at all scales from animals to cell cultures and bacteria. Yet, specific interactions with lipid membranes are more easily studied using model membranes. For instance, freeze-fracture electron microscopy allowed Radlinska et al. [15] to locate a polystyrene derivative inside a non-ionic surfactant bilayer. UV-visible spectroscopy can provide information about the local environment embedding nano-sized materials, while scattering techniques can give indications on the structural properties of nanoparticles – lipid mixtures. With appropriate labelling, other spectrometric methods can be used; for example, Ikeda et al. [16] used NMR spectroscopy to study the distribution of C60 fullerene in DPPC liposomes. Differential scanning calorimetry (DSC) or fluorescence anisotropy can give information on other membrane properties, such as phase transition temperatures and possible changes of the latter upon addition of nano-sized materials. Atomic force microscopy (AFM) allows probing membrane surface at nano-scale resolution. The range of biophysical tools to study the interactions of nanoparticles with membrane is thus very broad.
References
Luca Monticelli (CNRS) - Organiser
Italy
Gulia Rossi (Physics Department, University of Genova, Genoa, Italy) - Organiser & speaker
Switzerland
Julian Shillcock (EPFL) - Organiser
United Kingdom
Paola Carbone (University of Manchester) - Organiser