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The blood-brain barrier (BBB) is a biological border crossing that prevents undesirables (toxins, pathogens) in the bloodstream from passing through to the brain, while allowing oxygen and nutrients to pass freely. Like all our physiological systems, it has evolved in an environment that contains nanoparticles (between 1nm and 100nm in size), as they are produced naturally by Earth's geological processes. However, in the modern age, we've significantly increased the number and variety of nanoparticles in our environment and started to manufacture them deliberately for use in (e.g.) cosmetics and medicines.
After a previous study1 found that iron oxide nanoparticles from pollution are present in human brains, an international team of researchers started investigating whether the characteristics of nanoparticles - size, shape and composition - affect their ability to pass through the BBB.
Their results, recently published in PNAS, could help us design safer nanomaterials and develop new drug delivery systems to treat neurodegenerative diseases.
A tightly packed layer of endothelial cells essentially separates the brain from the rest of the body. This blood-brain barrier (BBB) allows oxygen and nutrients to pass to the brain and exists to deny passage to any harmful substances transported in the blood. Although that's usually a good thing, the BBB can make it tricky to administer drugs to treat brain issues such as neurodegenerative diseases.
Nanomaterials that we inhale, ingest or apply to our skin may reach the bloodstream. From there, some nanoparticles may make it to the brain side of the barrier, where they potentially have neurological effects.
In recent years, new techniques have allowed us to detect and investigate microparticles and now nanoparticles. When research showed that magnetite nanoparticles from pollution had crossed the BBB, a team of researchers began investigating what factors affect the ability of these tiny particles to enter the brain and whether they undergo a transformation when they do, or even so that they are able to cross the BBB.
In work recently published in PNAS, an international team of researchers worked with metallic engineered nanoparticles (ENMs). Their experiments involved cerium oxide, iron oxide, zinc oxide and silver in different particle sizes and shapes, and a well-established in vitro model comprised of two different types of real BBB cells, organised in a way to behave like the BBB.
Once they had completed these penetration tests, confirming that the model was a good analogue of the real barrier, the team brought the cells to Diamond to examine the number, distribution and chemical composition of nanoparticles that had crossed the BBB.
There are several challenging aspects to investigations of this sort. They involve actual cells, with their inherent squishiness, plus small concentrations of tiny particles. To get to the bottom of what was happening, the research team used biological assays combined with state-of-the-art analytical techniques – in the lab, for example, single-particle inductively coupled plasma mass spectrometry (spICP-MS) and at Diamond, synchrotron X-ray absorption fine structure spectroscopy (XAFS), and high spatial resolution scanning transmission X-ray microscopy (STXM).
Professor Eugenia Valsami-Jones, from the University of Birmingham, was the project Principal Investigator. She said:
Using XAFS on B18 allowed us to see the nanoparticles in their chemical environment. This is hugely important, as it means we can see which form the metals are in and whether they have changed form in order to cross the barrier. Collecting STXM data at I08 gave us a map of the cells, showing the spatial distribution and chemical states of the nanoparticles. Combining these two imaging techniques shows us which nanoparticles have passed the BBB, where they have ended up, and how they have changed.
The beamline staff at Diamond are wonderful, they're always on hand if you have a problem - even in the middle of the night! And they provided invaluable help with both XAFS and STXM. We were quite apprehensive about the STXM experiments, which was a new technique for us, but with their guidance the experiments worked.
The results show that the physiochemical properties of the nanomaterials affect how easily they penetrate the BBB. The results are different for different metals but also different compositions of the same metal. Smaller particles cross the BBB more easily, but their shape is also important. More elongated particles find it harder to cross the barrier, for example, compared with their spherical counterparts.
This research contributes to our fundamental understanding of interactions between nanomaterials and the brain. It will help us develop nanomaterials in safer ways, ensuring, for example, that if they become airborne, they cannot cross the BBB. And also, to tailor nanoparticles as drug delivery systems for (e.g.) neurodegenerative diseases such as Alzheimer's and Parkinson's.
Every in vitro model has its limitations, so the team are working on improved models. They're also investigating nanoplastics, a far more diverse and dynamics set of nanomaterials, and how they may cross the blood-brain barrier.
To find out more about the I08 beamline or discuss potential applications, please contact Principal Beamline Scientist Burkhard Kaulich: firstname.lastname@example.org. The Principal Beamline Scientist for B18 is Diego Gianolio: email@example.com.
Maher B et al. Magnetite pollution nanoparticles in the human brain. Proceedings of the National Academy of Sciences 113.39 (2016): 10797-10801.
Guo Z et al. Biotransformation modulates the penetration of metallic nanomaterials across an artificial blood-brain barrier model. Proceedings of the National Academy of Sciences 118.28 (2021). DOI:10.1073/pnas.2105245118.
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