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Posted: Jan 22, 2009
Cross-border nanotechnology - toxic effects of nanoparticles penetrating cells
(Nanowerk Spotlight) One of the major concerns regarding the potential risks of nanotechnology applications are possible toxic effects of nanoparticles. The concern is that these materials have the capacity to penetrate cells and potentially translocate to other cells, tissues and organs remote from the portal of entry to the body. This is considered to be a necessary step in the movement of particles deposited in the lung, entering the blood, acting upon cells in other tissues, manifesting ultimately in a physiological response.
The importance of translocation in nanoparticle toxicology has been the subject of a recently completed nanotoxicology research project called "Cell Pen", conducted by the Institute of Occupational Medicine in the UK together with a team of multi-disciplinary experts.
As with so many previous nanotechnology risk review reports, it appears that this documents highlight more the uncertainties and the unknown than what is actually known about the interaction of nanoparticles with cells. The authors write that "on the basis of current literature, it is premature to draw definitive conclusions". That in itself should be quite worrying. It clearly underlines the fact that, while the development of nanotechnology materials and applications pushes full steam ahead, there are not enough efforts being devoted to unequivocally determine the health and environmental impact of these materials.
The objectives of the Cell Pen project were to scope the research required into the mechanisms of translocation across the respiratory epithelium, and the resulting possible toxic effects in and beyond the lung, and advise on the feasibility of achieving the following outcomes:
1. Identifying which features of nano-particles/tubes/fibres are important in particle-cell interactions, considering the potential role of nanoparticle chemistry, structure, mass, numbers, shape, surface area, surface charge and surface functionalisation;
2. Suggesting how nanoparticles may be modified to enhance or reduce their capacity to enter cells;
3. Suggesting how interactions between nanoparticles and cultured human cells might be studied.
"Enhancing our knowledge of the physico-chemical properties which influence the efficacious, benign or toxic interaction between nanomaterials and cells will help inform our understanding of experimental observations and the design of engineered nanomaterials intended for particular applications" said Dr Steve Hankin, Senior Consultant at IOM & and lead author of the report.
The consortium behind the report was formed from members of SnIRC (the Safety of Nanoparticles Interdisciplinary Research Centre) – including IOM, Edinburgh University, Napier University Edinburgh & Central Science Laboratories, York.
Reviewing the available literature, the report highlights the existing knowledge and uncertainties regarding the interactions of nanoparticles and cells, the physico-chemical factors that influence translocation and the consequences of such interactions/translocation:
Size – article uptake by cells has been observed to be size and temperature dependent.
Specific surface area – the precise influence of specific surface area on particle uptake by cells has not been extensively reported. However, high specific surface area of particles is proven to enhance inflammation.
Surface chemistry – particle uptake by cells has been observed to be influenced by the chemical nature ofthe particle surface.
Charge – particle uptake by cells has been observed to be influenced by the particle’s charge.
The report concludes that "it is apparent from the literature reviewed that many findings are reported from studies which have not yet set out to investigate systematically the physicochemical factors which control the capacity of nanoparticles to penetrate cells. It is challenging to deconvolute the influence of any one physico-chemical factor on the cell penetration capacity of nanoparticles from such studies where multiple particle types and variables are reported (e.g. size, surface coating and charge). Furthermore, properties of nanoparticles such as surface chemistry or aggregation in biological or other fluids may not be in equilibrium or even at steady state and these properties may well change as a function of time."
"Modelling and the investigation of structure-activity relationships have been acknowledged as being in the infancy with further work required. These, along with more appropriately designed systematic studies, are required to elucidate the role of physico-chemical properties."
Whilst it was beyond the scope of this review to elucidate the basis of inconsistencies between studies and why some have not shown translocation from the lung to other organs where others have, the potential for translocation of nanoparticles has been established and a number of the influencing factors including physico-chemical properties (e.g. size, surface chemistry, charge), physiological mechanisms and preexisting disease within the population have been highlighted.
The recommendations from the project, which fall into two main areas, provide a framework for future studies to consider as priorities. The two areas are cross-cutting themes for translocation and penetration studies, and research requirements specific to aspects of penetration and translocation studies.
Cross-cutting themes for Cell Penetration & Translocation studies
Establishment of a clear definition for Cell Penetration of Nanoparticles
Development of well characterised NPs for use in future studies
Near-term preparation of widely available, suitably characterised ‘stock’ NPs for penetration & localisation studies, as well as toxicity studies
Development of suitable labelling systems for particle penetration/translocation studies
Use of a wide range of concentrations for toxicity studies to establish a doseresponse relationship that can be applied to the risk assessment process
Research priorities for nanoparticle translocation studies
Recommended research priorities for investigating interactions between NPs and cells include research to aid understanding of mechanistic toxicology (general study priorities; in vitro study priorities; and in vivo study priorities) and research to generate suitable hazard data for NP risk assessment.