Nanoparticle pinpoints blood-vessel plaques

A step toward identifying plaques vulnerable to rupture that causes heart attack and stroke
February 7, 2014

An artery with plaque buildup (credit: NIH)

A team of researchers led by scientists at Case Western Reserve University has developed a multifunctional nanoparticle that enables magnetic resonance imaging (MRI) to pinpoint blood vessel plaques caused by atherosclerosis.

The technology is a step toward creating a non-invasive method of identifying plaques vulnerable to rupture — the cause of heart attack and stroke — in time for treatment.

Currently, doctors can identify only blood vessels that are narrowing due to plaque accumulation. A doctor makes an incision and slips a catheter inside a blood vessel in the arm, groin or neck. The catheter emits a dye that enables X-rays to show the narrowing.

Programming to identify vulnerable plaques

But Case Western Reserve researchers report in the journal Nano Letters that a nanoparticle built from the rod-shaped tobacco mosaic virus, commonly found on tobacco, locates and illuminates plaque in arteries more effectively and with a tiny fraction of the dye.

More importantly, the work shows that the tailored nanoparticles home in on plaque biomarkers. That opens the possibility that particles can be programmed to identify vulnerable plaques from stable ones, something untargeted dyes alone cannot.

Steinmetz, a specialist in bioengineering plant viruses, teamed with Xin Yu, a professor of biomedical engineering, who specializes in developing MRI techniques to investigate cardiovascular diseases. They created a device that transports and concentrates imaging agents on plaques.

Elongated nanoparticles have a higher probability of being pushed out of the central blood flow and targeting the vessel wall compared to spheres. The elongated shape also allows more stable attachment to the plaque, the researchers said.

The virus surface is modified to carry short chains of amino acids, called peptides, that make the virus stick where plaques are developing or already exist. Luyt and Simpson synthesized the peptides.

“The binding allows the particle to stay on the site longer, whereas the sheer force is more likely to wash away a sphere, due to its high curvature,” said Yu, an appointee of the Case School of Engineering.

10,000 times more contrast, 400 times less chemical

The virus surface was also modified to carry near-infrared dyes used for optical scanning, and gadolinium ions (which are linked with organic molecules, to reduce toxicity of the metal) used as an MRI contrasting agent. They used optical scans to verify the MRI results.

By loading the surface with gadolinium ions instead of injecting them and letting them flow freely in the blood stream, the nanoparticle increases the relaxivity — or contrast from healthy tissue — by more than 10,000 times. That’s because the nanorod carries up to 2,000 molecules of the contrast agent, concentrating them at the plaque sites. Secondly, attaching the contrast agent to a nanoparticle scaffold reduces its molecular tumbling rates and leads to additional relaxivity benefit, the researchers explained.

While the view is better, they are able to use 400 times less of the contrast agent because it’s delivered directly to plaques.

The tobacco virus-based nanoparticle, they said, offers another advantage: Most nanoparticles that have been developed to carry contrast agents are based on synthetic materials, some of which may stay in the body a while.

The tobacco virus is made of protein, which the body is well equipped to handle and flush from the system rapidly.

Steinmetz and Yu, members of the Case Center for Imaging Research, are now proposing to take the work a step further. They want to tailor the nanoparticles to show doctors whether the plaques are stable and require no treatment, or are vulnerable to rupture and require treatment. A rupture sets off the cascade of events that lead to heart attack and stroke.

To do this, they must first find different biomarkers of stable versus vulnerable plaques and coat the nanoparticles with different peptides and contrast agents that enable the MRI to tell one from the other.

“Our understanding of vulnerable plaques is incomplete, but once we can diagnose vulnerable plaques from stable plaques, it will be a paradigm shift in diagnosis and prognosis,” Yu said.

In addition to using the technology to find vulnerabilities, it may also useful for delivering medicines and monitoring treatment, the researchers say.

Abstract for Nano Letters paper:

The underlying cause of major cardiovascular events, such as myocardial infarctions and strokes, is atherosclerosis. For accurate diagnosis of this inflammatory disease, molecular imaging is required. Toward this goal, we sought to develop a nanoparticle-based, high aspect ratio, molecularly-targeted magnetic resonance MR imaging contrast agent. Specifically, we engineered the plant viral nanoparticle platform tobacco mosaic virus (TMV) to target vascular cell adhesion molecule (VCAM)-1, which is highly expressed on activated endothelial cells at atherosclerotic plaques. To achieve dual optical and MR imaging in an atherosclerotic ApoE-/- mouse model, TMV was modified to carry near-infrared dyes and chelated Gd ions. Our results indicate molecular targeting of atherosclerotic plaques. Based on the multivalency and multifunctionality, the targeted TMV-based MR probe increased the detection limit significantly; the injected dose of Gd ions could be further reduced by three orders of magnitude compared to the suggested clinical use, demonstrating the utility of targeted nanoparticle cargo delivery.