The most important characteristic of nanoparticles that facilitates
medical usage is their very high surface area to volume ratio. If you cut a 1 cm
cube into 10^21 cubes with 1 nm sides, that keeps the total volume unchanged,
but increases the surface area by a factor of 10 million. This enormous
increase allows hollow nanotubes or nanospheres to be used as "Trojan horses",
loaded with drugs, antibodies, therapeutic small molecules, etc to great effect.
The other
unique property of nanoparticles is that they impose constraints on the
directions in which electrons spin in their orbits. Electrons are similar to
tiny bar magnets, with a surrounding magnetic field that corresponds to the
electron spin in an applied field. In iron oxide macoparticles (>20 nm in
diameter), for example, electrons spin in both directions, thus neutralising
each other's magnetic effect. OTOH, in iron oxide nanoparicles (<20 nm) all electrons spin in the same direction, and thus each tiny magnet has an additive effect, generating a much bigger magnetic field. This can be exploited in MRI scanners, for example. This particular property is mentioned here for interest and has no relevance to the example I am about to discuss below.
In January 2020, a team of scientists from Stanford published a study in Nature Nanotechnology that demonstrated that the build up of atherosclerotic plaques in the aorta of genetically engineered mice could be abolished by the use of nanotechnology. These mice had had both their Apo E alleles deleted, thus making them very prone to atherosclerosis. To understand how the scientists stopped plaque build up in these mice, we just need to understand a tiny bit of molecular biology.
Normal cells in the body carry a marker called CD47 on their surface that stops them from being "eaten" (phagocytosed) by macrophages. In apoptotic cells , this surface marker disappears, which is recognised by macrophages as an "eat-me" signal, allowing them to hoover up dead or dying cells, a process called efferocytosis.
The way CD47 prevents its bearer cell from being eaten is by binding to a ligand (something that ligates) called Signal Regulatory protein alpha (SIRP) on macrophages. When SIRP on macrophages is ligated, it activates a downstream enzyme called SHP-1. This latter is a phosphatase (removes phosphate), and belongs to a class of enzymes that in general, act as inactivating enzymes. In this case, it inactivates a type of myosin in the cytoskeleton of the macrophages, thus stopping it from eating the CD47 bearing cell.
What the Stanford team did, was to load carbon nanotubes with two things- firstly, an inhibitor of SHP-1, which would thus scupper the CD47-SIRP pathway, thus abrogating the "don't-eat-me" signal. Secondly they put in a fluorescent dye that would make it easy to track the involved cells through a process called flow cytometry.
But the scientists still had one problem. In previous animal experiments, where investigators had targeted CD47 on plaque cells from atherosclerotic areas with a specific monoclonal antibody to CD47, the antibody had killed lots of "innocent bystanders" such as red blood cells in the spleen, which also carry CD47. You see, macrophages carry something called Fc receptors, which bind to the Fc portion of antibodies and destroys anything that the antibody itself is attached to (in this case, the red cells). This led to quite troublesome anaemia in these original experimental animals.
This is where the genius of carbon nanotubes was exploited by the Stanford team. Because of the tiny size of these nanotubes (called single walled nanotubes or SWNT), they are taken up by 99% of inflammatory monocytes. It is these activated monocytes which recognise the hallmark inflammation in atherosclerotic plaques, enter them and are converted into active macrophages. By contrast, the SWNT are taken up by <3% of other immune cells. The upshot is that normal healthy cells carrying CD47 are largely spared.
Furthermore, the scientists coated the nanotubes with a substance called PEG (polyethylene glycol). PEG is the same stuff that will be familiar to doctors as a powerful purgative, and therefore used in bowel preparation, the same stuff that is attached to drugs such as beta-interferon (in the treatment of multiple sclerosis) or to Certolizumab (in the treatment of rheumatoid arthritis), to prolong the action of these drugs. PEG is hydrophilic and therefore allows intravenous injection into blood.
The results were good. Atherosclerosis was prevented in these experimental mice despite their genetic vulnerability.
The concept extends way beyond the heart. Many cancerous cells try to evade the immune system by expressing CD47 on their surface. They can be similarly targeted if a way of selecting them out can be found (perhaps through hypoxic metabolism, as they display the Warburg phenomenon?).
It is worthwhile ending by mentioning that the inflammatory nature of atherosclerotic plaques has been previously targeted in trials of an interleukin-1 (IL-1) antagonist (these are also used to treat severe and refractory gout where other agents have failed). Unfortunately, the limiting side effect was serious infections, as IL-1 is a vital cytokine for the innate immune system. This is where the selectivity of carbon nanotubes was highlighted through the study.
Reference:
1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7254969/pdf/nihms-1546057.pdf
2. https://www.nejm.org/doi/pdf/10.1056/NEJMra0912273?articleTools=true
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