Nanoparticle Research Better understanding of nanoparticles: Small Gold with a Big Future

Gold nanoparticles can be used in a variety of ways, i.e. as active ingredient carriers in medicine. Although their synthesis is already very successful today, it is difficult to predict how the particles interact with the environment and humans. Scientists are therefore intensively investigating the behaviour of nanoparticles in order to make them more efficient and safer.

In the last 30 years, a range of scientific fields have benefited from our ability to manipulate and control nanoparticles. The relatively new field of nanotechnology is featuring more in our daily lives and has massive potential for the future. It is transforming science — from creating entirely new materials, to understanding the structures behind unusual scientific properties.

Nanoparticles are defined as particles between one and 100 nanometres in size, and can either be artificially produced or found in natural systems (for example as part of biological systems such as viruses or bone matrix). They range from carbon-based nanomaterials like fullerenes, to metal-based, such as silver and gold nanoparticles, to nano-polymers.

Multiple variables can be altered to define the properties of nanoparticles, offering engineers greater flexibility when designing materials to be used in our everyday lives. Nanomaterials are already used in everything from golf clubs to racing cars, and are also found in sun creams and cosmetics. The small size of the particles means they have a very high surface area to volume ratio, and thus their properties depend strongly on their size, shape and bound molecules. Nanoparticles have exciting possibilities in pharmaceuticals, as potential drug delivery vehicles and contrast agents.

A cautious step forward

While scientists have been able to fine-tune and engineer the properties of nanoparticles by changing their size, shape, and surface chemistry, predicting and controlling exactly how the particles behave at such a minute scale is an enormous challenge. This is of particular concern when it comes to using nanoparticles within the human body, or in systems where they could impact on the surrounding environment. While nanotechnology has improved lives and enabled massive progress in many areas of society, it must be acknowledged that until we are able to fully characterise their precise behaviours at every level, we cannot identify how far engineered nanomaterials expose humans, animals, and the environment to risk.

Golden delivery

Gold nanoparticles (AuNPs) are a metal-based material proving to be a next-generation tool in nanoengineering. Thanks to their particular range of electronic, optical, sensing, and biochemical properties, AuNPs have long-been investigated for potential biological and medical applications, such as medical imaging, disease treatment, and drug delivery processes. AuNPs can be visualised as a cluster of gold atoms at the centre, surrounded a molecular layer on the surface. This surface can be manipulated to produce particular functions for the nanoparticle as a whole, through the addition of specific ligands that may target a particular type of molecule.

By exploiting this property, gold nanoparticles can make good carriers of large and small molecules, hence the interest in employing them as drug transporters to human cells. The idea of nanoparticle-based drug formulations provides a potential opportunity to address and treat challenging diseases.

Nanotechnology has proven beneficial in the treatment of cancer, aids and many other conditions, also providing advancement in diagnostic testing. The nanoparticles can be developed into smart systems, encasing therapeutic and imaging agents, but gold in particular is thought to be suited to systems that can deliver drugs to specific tissues and provide controlled release therapy. Such systems enable researchers to resolve the main critical issues encountered with conventional pharmaceutical treatments such as the nonspecific distribution, rapid clearance, uncontrollable release of drugs, and low bioavailability. The sustained and targeted drug delivery which could be provided by AuNPs would minimise the toxicity associated with many drugs, and the lack of excess substance means that patients can rely on less frequent doses.

However, predicting exactly how far these nanoparticles are ab- sorbed by the cells, central to their toxicity, is very difficult. As such, so is understanding any potential associated risks to health through using these nanomaterials in the human body.

Scientific partnership

A collaboration of researchers examined this further. Scientists from the Institut Laue-Langevin (ILL), Tampere University, University of Helsinki, Norwegian University of Science and Technology, and Université Grenoble Alpes, investigated the physical and chemical influences when gold nanoparticles interact with a model biological membrane.

Identifying the behavioural mechanisms taking place is vital for applying gold nanoparticles in medicine. Enhancing our understanding of the factors that determine whether nanoparticles are attracted or repelled by the cell membrane, whether they are adsorbed or internalised, or whether they cause membrane destabilisation, will help us to ensure that nanoparticles interact with our cells in a controlled way. Such atomic-level intricacies could be the difference between a drug being effectively delivered to a site and carrying out the desired effect, or a drug being unintentionally absorbed into cells, causing systematic damage.

As outlined in the journal Small, the researchers used a combination of neutron scattering techniques and computational methods to study the interaction between positively charged cationic gold nanoparticles and model lipid membranes, with the aim of revealing the possible nanotoxicity.

Nanotoxicity studies are of great complexity, partly due to the fact that in vitro observations of toxicity are often not representative nor directly transferable to in vivo studies. The results obtained in this study could help to lay the foundations for further levels of investigation into how gold nanoparticles behave in the body.

Lipid membranes, found in a continuous bilayer around all cells, act as a key barrier that keeps out or allows in selected ions, proteins, and other molecules when needed, and prevents the organelles of the cell from diffusing out. The study showed how the temperature and the charge of lipids in the membrane are clear factors that modulate the presence of energy barriers affecting the interaction of the nanoparticle with the membrane.

The lipid charge is highly relevant for biological systems as plasma membranes are inherently negatively charged: this is critical to the effectiveness of ion pumps that move charged atoms in and out of the cell, creating polarisation central to the primary function of many cells. Understanding how the molecular mechanisms are influenced by temperature can be valuable as they can indicate how the natural biological system may be affected by varying temperature fluctuations. This understanding can then be used to tune the system across the phase of the lipid bilayer in the experimental environment. The results demonstrate how the presence of charged lipids determines the fate of AuNP — whether it is adsorbed or internalised by the cell — and how the AuNP-interaction responds to temperature in the case of non-charged and negatively charged bilayers.

A computational approach

Using the computational technique of coarse-grained molecular dynamics (MD), the study shows how the lipid charge can affect the cooperative behaviour, or aggregation, of AuNPs. It was found that negatively charged lipid can favour the aggregation of nanoparticles, a cooperative effect that can be fatal for the membrane stability. Furthermore, different molecular mechanisms for nanoparticle-membrane interactions were revealed that explain how nanoparticles become internalised in the lipid membranes.

Neutron reflectometry was the chosen technique for this study. It provides a wealth of information on the structure of thin films and solid surfaces, and is particularly well suited to the study of interfaces between solids and liquids. The technique is highly versatile, able to examine a wide variety of materials. It is the perfect tool for examining the molecular details of the lipid/nanoparticle interaction, providing unambiguous insight into the behaviours of the molecular components.

Institut Laue-Langevin (ILL) is the world’s flagship neutron science facility, and provides the tools for scientists from across the globe and all scientific fields to further investigate the structures at the centre of their research. The D17 instrument at ILL is a horizontal scattering geometry designed for high flux and flexibility, it is one of the facility’s two reflectometers, and is well suited to the study of solid-liquid interfaces and membranes.

In addition to the neutron reflectometry data, the researchers implemented Molecular Dynamics (MD) — a computational simulation method for studying the movement of atoms — to demonstrate how gold nanoparticles interact within the system at the atomic level. It provides a complementary tool to interpret and explain the data obtained on real systems by neutron reflectometry. The study indicates the potential destructive effects of gold nanoparticles on the cell membrane, as well as how a combination of neutron scattering and computational methods provides researchers with a much better understanding of the mechanisms at play.

A bright future for the field

First contact between a nanoparticle and a living cell occurs through a biological membrane, so it is extremely important to understand what is governing the interaction with the plasma membrane.

However, real membranes are complex in terms of their structure, composition, and properties (for example, presence of several lipid types, cholesterol, membrane proteins, glycocalyx). It is difficult to establish models that can predict the fate of nanoparticles interacting with a real plasma membrane or outline the effect of the interaction on the membrane structure and stability. Instead, simpler models can be used to represent some essential membrane characteristics.

Computational and neutron techniques have together provided a clearer indication of what influences the behaviour of nanoparticles. This can help us predict how cells will interact with nanoparticles in future applications. Research into the possible mechanisms for implementing gold nanoparticles in medical applications such as drug delivery must be accompanied by a wealth of studies into where the high-potential properties could also have extensive yet unwanted effects.

It is also important to ensure we develop the tools to investigate further — to ensure nanoparticles can be applied both effectively and safely. Developments in neutron science techniques and advances in sample environment and preparation, performed at world-class facilities such as ILL, are helping us to reach this point.

* Giovanna Fragneto, Institut Laue-Langevin, 38042 Grenoble/France,

* * Marco Maccarini Université Grenoble Alpes

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