Patients with narrowed arteries who don't qualify for drug-eluting stents could have their ailing blood vessels aided by teams of sticky nanoparticles, dubbed nanoburrs, according to a study published this week in the Proceedings of the National Academy of Sciences.

Like burrs, the seeds that get caught on your clothes outside, "nanoburrs" bristle with tiny hooks, making them adept at clinging to exposed surfaces of wounded arteries. When ferrying an anti-proliferative drug, the 60 nm-wide nanoburr could help people whose arterial lesions' number or size make them inappropriate for treatment with stents. It could also be used as a back-up for drug-eluting stents by delivering the drug to regions surrounding the stent struts.

"There may be some instances when a drug-eluting stent is less suitable for a patient," Juliana Chan tells DOTmed News. Chan is a Ph.D. student in biology at MIT and co-author of the study with Omid Farokhzad, associate professor of anesthesiology at Harvard Medical School and Robert Langer, a professor of chemical and biomedical engineering at MIT.

Patients often denied treatment with drug-eluting stents include those with renal failure, those with arterial lesions bigger than 3.5 mm or smaller than 2.5 mm, those who need multiple stents in a single artery, and those with so-called bifurcation lesions, where plaque builds up at the site where the artery splits in two, which is where the stent is less easily crimped, according to Chan.

HOW IT STICKS

The nanoburrs latch onto injured arterial walls because they're decorated with peptides pulled from bacterial phages, viruses that infect bacteria. The researchers combed through a phage library, screening for a peptide that would help the burr stick to arteries, and they found one: a peptide that latches onto the collagen that makes up the basement membrane of arteries. What makes this peptide useful is that it preferentially binds to the basement membrane of the artery wall that gets exposed whenever the artery is injured, such as during an angioplasty, where the inflated angio balloon squeezes against the arterial wall, pulling off the top layer of cells.

The nanoburr's stickiness means these tiny hybrid-polymeric particles are much more likely to hit the treatment target than nanoparticles lacking the protein hooks. In the current study, done in both arterial cell cultures in a dish and in the carotid arteries of living rats, the burred nanoparticles were between two and four times as likely to glom onto injured arterial tissue as non-burred varieties.

LONG-TERM DOSING

The particle's ability to stick to the artery wall contributed to one of its main potential clinical benefits: steady, long-term dosing.

Although it's too early to know how successful the treatment could be, Chan says by lengthening the polymer chain you could slow down the release of the anti-proliferative drug.

"In blood, particles are eroding slowly, and the chain is being cut, and the drug is being released," she explains. "If you can get a really long chain, you might have a very slow and low drug release."

Currently, the team has gotten dosing to a steady drip over around 12 days.

"In order to be competitive or potentially useful, it needs to be able to release over at least a couple of days or a week," Chan adds.

FATTY COATING

Critical to keeping the nanoburr sticking and circulating in the blood for a long time is another aspect of its structure: its protective fatty and chemical coatings.

The body's natural defenses will quickly muster attacks against foreign particles. To ensure this doesn't happen with the burrs, the researchers sheathe them in soy lecithin, a fatty substance, and coat them with polyethylene glycol (PEG). PEG, being so inert and hydrophilic, is able to evade much of the body's defenses, and has become the substance of choice in designing nanoparticles for medical applications, according to Chan. Studies begun in the early '90s have shown that "with PEG, you can increase circulation [of a polymeric nanoparticle] from five minutes to days," she explains. "PEG is the holy grail of polymeric nanoparticles."

FIGHTING TUMORS

Although the current study tested the nanoburrs on arteries, Chan says they could also have a role in fighting tumors.

"Most tumors have really poor, irregular and leaky vasculature," Chan notes. Nanoburrs could preferentially target the pockets between damaged layers of the arteries recruited by tumors, letting them slip into the leaky vessels while bearing a cancer-killing drug as payload.


UPCOMING STUDIES

Before testing the burrs' chances against cancer, Chan is hoping to try the effectiveness of the technique in blocking restenosis in animals. In the current study, when the nanoburr was injected in rats, the researchers replaced paclitaxel, the anti-proliferative drug used in stents, with a fluorescent dye so they could easily image how well it stuck to injured arteries. Now they want to see how the nanoburr actually works by comparing treatment with a drug-bearing nanoparticle to one with a sham saline solution.

"I think there are a lot of options right now," Chan says.