Multifunctional Nanoparticle Targets Blood Vessel Plaques

The technology is a cutting-edge way of identifying plaques susceptible to rupture—the cause of heart attack and stroke—in time for treatment.

Currently, physicians can identify only blood vessels that are narrowing due to plaque accumulation. A doctor makes an incision and places a catheter inside a blood vessel in the arm, groin, or neck. The catheter emits a dye that enables X-rays to reveal the narrowing. However, Case Western Reserve University (Cleveland, OH, USA) researchers reported online February 7, 2014, in the journal Nano Letters that a nanoparticle built from a rod-shaped virus typically found on tobacco pinpoints and illuminates plaque in arteries more effectively and with a tiny fraction of the dye.

The research, more significantly, shows that the customized nanoparticles home in on plaque biomarkers. That creates a way for that particles can be programmed to identify vulnerable plaques from stable, something untargeted dyes alone cannot. “From a chemist’s point of view, it’s still challenging to make nanoparticles that are not spherical, but non-spherical materials are advantageous for medical applications,” said Dr. Nicole F. Steinmetz, assistant professor of biomedical engineering at Case Western Reserve. “Nature is way ahead of us. We’re harvesting nature's methods to turn them into something useful in medicine.”

The rod-shaped nanoparticles are made from Tobacco mosaic virus, tiny tubular organisms that infect plant cells but are benign outside the plant. Dr. Steinmetz, a specialist in bioengineering plant viruses, teamed with Dr. 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 chance of being thrust out of the central blood flow and targeting the vessel wall compared to spheres. Further, the shape allows more stable attachment to the plaque, according to the investigators.

The virus surface is engineered to carry short chains of amino acids, called peptides, that make the virus stick where plaques are developing or already exist. Drs. 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 Dr. Yu, an appointee of the Case School of Engineering.

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 findings. By loading the surface with gadolinium ions instead of injecting and letting them flow freely in the blood stream, the nanoparticle increases the relaxivity (contrast from healthy tissue) by more than four orders of magnitude. “The agent injected in the blood stream has a relaxivity of 5, and our nanoparticles a relaxivity of 35,000,” said Dr. Steinmetz who was appointed by the Case Western Reserve School of Medicine.

That is 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 is delivered directly to plaques. The tobacco virus-based nanoparticle, they said, offers another benefit: 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 mosaic virus is comprised of protein, which the body is can easily handle and clear from the system rapidly. Drs. Steinmetz and Yu, members of the Case Center for Imaging Research, are now planning to take the research even further. They want to customize the nanoparticles to show doctors whether the plaques are stable and require no treatment, or are vulnerable to rupture and require treatment. A rupture initiates the cascade of events that lead to heart attack and stroke.

To achieve this, the scientists have to first find different biomarkers of stable instead of vulnerable plaques and coat the nanoparticles with different peptides and contrast agents that enable the MRI scanning to identify 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,” Dr. Yu said.

The new technology may also useful for delivering medicines and monitoring treatment, in addition to using it to find vulnerabilities, according to the researchers.

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