Nanoparticles to Target Atherosclerotic Plaques

This popular science article takes a look at efforts to develop nanoparticles capable of reducing the size of plaques in blood vessels produced by the processes of atherosclerosis. These plaques narrow and deform blood vessels, ultimately breaking apart to cause blockages and ruptures of blood vessels that are often fatal. Atherosclerosis is caused at root by damaged lipids that enter the circulation and lodge in blood vessel tissue. This is followed by an unfortunate set of self-reinforcing signals sent by cells in the blood vessel wall and then by immune cells that turn up to try to deal with the problem. When immune cells become overwhelmed by ingesting damaged lipids, their destruction produces yet more debris, and plaques consisting of lipids and dead cells grow. Chronic inflammation can also accelerate this process, and aging is characterized by rising levels of inflammation. Treatments like the one profiled in this article do not treat the root causes of the problem, but regardless of success in addressing those root causes, large plaques will still need to be removed in people old enough to have developed them:

Careening through the bloodstream, a single nanoparticle is dwarfed by red blood cells whizzing by that are 100 times larger. But when specially designed nanoparticles bump into an atherosclerotic plaque - a fatty clog narrowing a blood vessel - the tiny particles can play an outsized role. They can cling to the plaque and begin to break it down, clearing the path for those big blood cells to flow more easily and calming the angry inflammation in the vicinity. By finding and busting apart plaques in the arteries, nanoparticles may offer a new, non-surgical way to reduce a patient's risk for heart attack and stroke. Some nanoparticles home in on the plaques by binding to immune cells in the area, some do so by mimicking natural cholesterol molecules and others search for collagen exposed in damaged vessel walls. Once at the location of a plaque, either the nanoparticles themselves or a piggybacked drug can do the cleanup work. Today, cardiovascular nanoparticles are still far from pharmacy shelves. Most have not reached safety testing in patients. But in mice, rats and pigs, nanodrugs have slowed the growth of the plaques that build up on vessel walls, and in some cases have been able to shrink or clear them. "I think the effect we can have with these nanoparticles on cardiovascular disease is even more pronounced and direct than what we've seen in cancer."

Many of the immune cells involved in atherosclerosis are macrophages, white blood cells that gulp pathogens, dead cells or debris in the body. At the site of a plaque, macrophages become swollen with fats and transform into what are called "foam cells" because of their foamy appearance. As they digest fats, foam cells send out chemical signals to recruit more inflammation-causing cells and molecules to the area. Because they're so intimately involved in the formation of plaques, macrophages and foam cells are a prime target for nanoparticles. One research group has designed nanoparticles that bind to molecules on the surface of macrophages, preventing them from gobbling fats and becoming foam cells. The researchers made the nanoparticles specifically target a subtype of macrophage that's involved in atherosclerosis, not the macrophages that might respond to other injuries in the body. When nanoparticles were injected into mice with narrowed arteries, the blockages decreased by 37 percent.

Another research group has designed HDL-mimicking nanoparticles. The particles deliver statins that make a beeline for macrophages and plaques, letting them administer the drug at lower-than-usual doses. The researchers were inspired by earlier studies that showed how extremely high doses of statins, given to mice, could lower LDL levels while also packing anti-inflammatory properties. Of course, in humans, such high doses would probably cause liver or kidney damage. The solution: tack the statins to a nanoparticle to send them, missile-like, to the plaques. That way, a low dose of the drug could achieve the high concentration needed at the site of the atherosclerosis. The group reported that plaque-filled arteries in mice given the nanoparticle were 16 percent more open than arteries in mice with no treatment, and 12 percent more open than in mice given a systemic statin.

The inflamed vessel wall around an atherosclerotic plaque goes through several changes in addition to the accumulation of belligerent immune molecules. As vessel walls are stretched and inflamed, the structural protein collagen, meant to keep the vessels taut and tubular, becomes exposed the way the threads of a tire begin to appear as it wears down. Scientists are using the exposed collagen to their advantage. Their nanoparticle combines a collagen-binding protein with nitric oxide, a molecule that stimulates the growth of new cells at wounds. To maximize the surface area of the drug that contacts the vessel wall, the team arranged the molecules in a line, forming a nanofiber, rather than a sphere. As the fiber is swept through the bloodstream, it binds to exposed collagen, anchoring the nitric oxide in place to spur healing of the artery. The researchers added fluorescent tags to the nanofibers and showed that the fibers congregated at injured spots on mouse arteries within an hour of injection. The tagged particles remained there for three days and the treated vessels ended up 41 percent more open.



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