A new paper published on-line today in Nature Nanotechnology hints that some nanoparticles could cause damage to cells on the other side of normally tight barriers – such as the blood brain barrier or the placenta – without actually crossing the barriers.  It’s a study that could raise concerns over the safe  medical use of nanoparticles, at a time when the first human trials of “smart nanoparticle” therapeutics are being discussed.

Using an artificial system designed to investigate cellular barriers, Gevdeep Bhaba and co-authors show that high concentrations of Cobalt-Chromium alloy nanoparticles on one side of a tightly meshed layer of cells can cause measurable DNA damage to cells on the other side.  And they seem to do this without actually crossing the cellular barrier.

I’m not sure how much attention this paper will get, but given its apparent relevance to harm occurring across the placental barrier, there could be some pickup beyond the usual scientific outlets.  And interestingly, it is being published at the same time as the first human trials for a “smart nanoparticle” based cancer therapy are being reported – that’s a juxtaposition that could drive a substantial amount of interest in the research.

As I was asked to comment on it prior to its release, I thought it worth jotting some notes down here on the work, just in case anyone’s interested (I’ll be in the thick of a workshop on emerging technologies and emerging economies when the paper is published on-line, so this post is being written some time ahead of it going live).

In brief, the paper (Nanoparticles can cause DNA damage across a cellular barrier, by Gevdeep Bhaba et al., Nature Nanotechnology. DOI: 10.1038/NNANO.2009.313) describes a set of experiments carried out using an artificially grown layer of cells on a porous support.  The cells (BeWo cells for the interested, derived from a human trophoblast choriocarcinoma cell line) were grown as a multi-layered barrier, to simulate tight barriers in the body like the placental barrier.  On one side of this layer of cells were placed human fibroblast cells.  On the other side, Cobalt-Chromium alloy particles (CoCr particles) were placed.  Following introduction of the particles, the fibroblasts were checked for DNA damage using an alkaline comet assay.

Schematic of the system used by Bhabra and colleagues to investigate the potential for CoCr particles to cause DNA damage across tight cellular barriers (Nature Nanotechnology, DOI: 10.1038/NNANO.2009.313)

Schematic of the system used by Bhabra and colleagues to investigate the potential for CoCr particles to cause DNA damage across tight cellular barriers (Nature Nanotechnology, DOI: 10.1038/NNANO.2009.313)

As you would expect in a good study, DNA damage was measured under a number of conditions, to identify what was going on.  Nanometer-scale and larger CoCr particles were used to see whether size was important.  Cobalt and Chromium ions were also used, to see whether the presence of dissolved metals was significant.  Particles were also introduced directly to the fibroblasts, to see what happened in the absence of the cellular barrier.  In addition, the concentration of Cobalt and Chromium was measured below the cellular barrier to see how much stuff (if any) got through.  And the barrier cells were treated with agents designed to block different transmission routes for certain substances, to get a handle on whether DNA damage was being caused by stuff penetrating through the barrier, or being generated (and subsequently released) from within the barrier.

The upshot of all this was that the researchers found evidence that placing Cobalt or Chromium one one side of the barrier caused measurable DNA damage in the fibroblasts on the other side, and that the damage seemed to be associated with chemicals generated within the cellular barrier by the metals.  In other words, the combination of CoCr particles and cellular barrier seemed to lead to DNA damage the other side of the barrier, even though the particles didn’t cross it!

The authors of the paper conclude:

We suggest that an evaluation of nanoparticle safety should not rely on whether they fail to gain access to privileged sites.  Instead there should also be an evaluation of their genotoxic potential for both direct and indirect effects to avoid any potential risks to targets on the distal [far] side of cellular barriers.

However, while this is an interesting paper, it wold be dangerous to speculate too far on what its relevance to nanoparticle safety.  When asked to comment briefly on the paper by the Science Media Center in the UK, this is what I wrote:

This is a study that raises an intriguing question – can foreign materials in the body cause harm across barriers like the placenta and the blood-brain barrier without actually crossing the barriers?  Evidence is presented that suggests there is some possibility of this occurring.  But the results should be treated with a high degree of caution until more is known.  In particular:

The effects seen are do not seem to be confined to nanoparticles alone.  There is some evidence that even large particles containing Cobalt and Chromium – the two specific materials studied here – can exert their influence across barriers in the body.

No evidence is presented to suggest that this is a way in which all nanoparticles can cause harm, as opposed to the specific types of nanoparticles tested.

From these results, it is not possible to say whether the observed effects could occur under real-life conditions, or whether harm could be caused at realistic exposure levels.  The concentrations of material used were very high – the equivalent of the placenta in a 9 months pregnant woman being exposed to approximately 4 – 40 grams of material. Whether such high exposures to materials like the ones used will ever occur is questionable.

While the study opens up new avenues of research, and should be of particular interest to scientists developing new nanoparticle-based drugs and medical devices, it is too early to say whether materials in the body – including nanomaterials – are likely to cause damage across normally tight barriers like the placenta.

In other words, a fascinating piece of science that raises the possibility of a novel way in which materials could cause harm, but which sheds little light on the likelihood of this being a significant concern from real products in real people.

The bottom line here is that, while this is a scientifically interesting study, it is far removed from implying that specific types of nanoparticles in the body could actually cause significant harm in this way.  Certainly, it suggests more research is needed in this area – especially as an increasing number of drugs and medical devices are developed that rely on nanoparticles, and as these products enter the human trials phase.  But at the moment, the data do not support nanoparticle-related DNA damage across the placenta (or any other tight biological barrier) as being a probable cause of serious harm.

Andrew Maynard