Nanoparticles used to treat damaged arteries

“New trials suggest microscopic stealth drones could be used to seek and repair damaged arteries," The Daily Telegraph, somewhat overexcitedly, reports.

A study in mice has found promising results for a targeted treatment where nanoparticles are used to deliver a "repair protein" to sections of arteries affected by atherosclerosis.

Atherosclerosis occurs when fatty material collects in the lining of arteries, causing inflammation. The body tries to repair this, covering the areas with fibrous tissue, creating "plaques". Continued fatty build-ups collect on these plaques and eventually the repair system fails, and the plaques rupture. This may cause a blood clot to enter the circulation and cause a heart attack or stroke.

In this study, researchers have identified a protein called annexin A1, which is usually part of the repair process. They took a section of this protein and covered it in a nanoparticle (a microscopic particle). They then attached proteins to the surface that would "stick" to the plaques.

The nanoparticles targeted the plaques in mice with advanced atherosclerosis, where they slowly released the section of annexin A1, which helped to improve the repair system. 

Further studies in pigs and then primates are now planned. If successful, human trials may then be conducted.

Where did the story come from?

The study was carried out by researchers from Colombia University in New York, Brigham and Women’s Hospital in Boston, and Barts and the London School of Medicine. It was funded by the US National Institutes for Health, the Wellcome Trust and the David Koch Prostate Cancer Foundation. The authors have disclosed a competing interest, in that an international patent has been filed for the inflammatory resolving nanoparticles.

The study was published in the peer-reviewed journal Science Translation Medicine.

We suspect that somebody at The Daily Telegraph has been reading too much science fiction, which led to their description of "microscopic stealth drones". Microscopic? Yes. Stealth drones? No.

That aside, the media reported this study accurately, though descriptions of nanoparticles "mending" or "repairing" damaged arteries, are not exactly what occurred. The new technique helped to stabilise plaques and reduce the damaging inflammation, but did not remove them.

What kind of research was this?

This was an animal experiment, which aimed to test a new technique to resolve atherosclerotic plaques.

Atherosclerosis (hardening and thinning of the arteries) occurs when fatty material collects in the lining of arteries, causing inflammation. This in turn causes the body to try to repair the area by forming a protective fibrous tissue over the top. These areas, called plaques, continue to build up and restrict blood flow. Eventually, the inflammation continues, but the repair process stops working. The plaques then have a thin layer of this fibrous tissue and so are more likely to rupture, causing a blood clot to break off, which can lead to a stroke or heart attack.

Prevention of atherosclerosis involves a healthy diet, not smoking, and doing exercise, though plaques may still develop. Current treatments aim to reduce the amount of cholesterol in the blood using statins, treating high blood pressure to reduce the likelihood of a plaque rupturing, and drugs such as aspirin to thin the blood and prevent it sticking to the plaques and causing a clot.

The researchers' main aim was to find a way to reduce the inflammation that is occurring within the plaques as an additional treatment strategy. Other novel attempts, such as with genetic manipulation or immunosuppressant drugs, dampen down the whole immune system, leaving it vulnerable to infection. This new technique, using targeted nanoparticles, means that a limited amount can be circulated in the bloodstream, without affecting the normal immune response.

What did the research involve?

The researchers isolated a human protein called annexin A1, which normally helps to resolve inflammation. They took a component of this, called Ac2-26, and covered it in a nanoparticle, which is a microscopic particle with a diameter of 100 nanometers or less. They attached peptides to the surface of these nanoparticles that would effectively "stick" to the plaques.

They injected mice with advanced atherosclerosis once per week for five weeks with either these nanoparticles, a scrambled version of the nanoparticles, Ac2-26, or a control of normal saline (salty water). The researchers then looked at the first part of the aorta (the main artery taking oxygenated blood from the heart to the body) and the main artery that supplies the brain.

What were the basic results?

The nanoparticles stuck to the plaques and released the Ac2-26 proteins. Compared to the other mice, those given the nanoparticles had:

• increased collagen (the protective fibrous layer covering the plaques)
• reduced reactive oxygen species (these accumulate during acute inflammation, but an excess amount can damage tissues)
• increased anti-inflammatory cytokines (communication cells of the immune system)
• 80% reduced area of plaque necrosis (breakdown)

In short, this acted to resolve the inflammation and stabilise the plaques. These changes were not present in the spleen or liver, indicating that the nanoparticles were likely to have just targeted the plaques.

How did the researchers interpret the results?

The authors concluded that their animal experiments "tested a proof-of-concept targeted NP [nanoparticles] with one type of proresolving mediator. To bring targeted resolution mediator nanotherapeutics to the clinic for patients at high risk for atherothrombotic vascular events, additional confirmatory studies will be needed, including evaluation in more predictive models, such as fat-fed pigs and non-human primates". They also acknowledge that "detailed toxicity studies will be needed to show the safety of both the NP material and the resolution mediator cargo".

Conclusion

This exciting study in mice has shown that nanoparticles can be manufactured to target the plaques that form in atherosclerosis, and help stabilise them. It appears that the nanoparticles honed in on the plaques, rather than affecting other organs such as the spleen or liver, which gives an early indication that there may not be substantial side effects. However, it will be necessary to see if the same holds true for other organs.

As with all mice studies, they give an indication of the likely biological effects of a new technique, but they do not provide the full picture of what may happen in humans, especially with regards to more subtle side effects.

The media have rather exaggerated the results of this study by claiming the technique repaired arterial damage. This is not the case; the nanoparticles were able to help stabilise the plaques and reduce the inflammation that is part of the process of plaque formation. However, the study did not show that the arteries went back to normal. The plaques were still present. This technique, if possible in humans, would be an additional strategy for "damage limitation" of atherosclerosis.

Researchers now plan to see if the techniques work in animals with more complicated bodies and biological systems, such as pigs and primates. If these hurdles are successfully passed, human trials may then begin.

Currently, the best way to slow down or try to prevent atherosclerosis is to lead a healthy lifestyle and reduce known risk factors.

This includes stopping smoking, weight management and regular exercise. In some cases, cholesterol-lowering medications, such as statins, and blood-thinning medications, such as low-dose aspirin, may also be recommended.