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Lola Eniola-Adefeso and student Alex Thompson discuss the results of an experiment determining how well potential drug carriers bind to blood vessel walls.Many medically-minded researchers are in hot pursuit of designs that will allow drug-carrying nanoparticles to navigate tissues and the interiors of cells, but chemical engineering professor Omolola Eniola-Adefeso and her team discovered that these particles have another hurdle to overcome: escaping the bloodstream.

Drug delivery systems promise precision targeting of diseased tissue, meaning that medicines could be more effective at lower doses and with fewer side effects. Such an approach could treat plaques in arteries, which can lead to heart attacks or strokes. Drug carriers would identify inflamed vessel walls and deliver a drug that removes the deposits of calcium, cholesterol, and other substances. Or, the carriers might seek out markers of cancer and kill off the small blood vessels in tumors, starving the malignant tissue of food and oxygen.

Nanoparticles, which have diameters under one micron, or one thousandth of a millimeter, are thought to be the most promising drug carriers. Eniola-Adefeso, who studies nanoparticles in flowing blood, explained that the immune system can’t get rid of them quickly. “It’s hard for a white blood cell to understand that it has a nanoparticle next to it,” she said. Those same tiny dimensions allow them to slip through the cracks between cells and infiltrate cell membranes, where they can go to work administering medicine.

But Eniola-Adefeso and her team found that these particles have an Achilles heel. Blood vessels are the body’s highways, and once nanoparticles get into the flow, they find it very difficult to reach the exits.

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Targeting disease with nanoparticles

Monday, February 4, 2013 3:31 p.m.

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Nanoparticles, which are popular candidates for ferrying drugs to target locations in the human body, have been shown to evade the immune system and infiltrate tissues and cells. But, Michigan Engineering Professor Lola Eniola-Adefeso and her team discovered they’re no good at leaving the bloodstream, getting trapped instead by red blood cells.

Nanoparticles, which are popular candidates for ferrying drugs to target locations in the human body, have been shown to evade the immune system and infiltrate tissues and cells. But, Michigan Engineering Professor Lola Eniola-Adefeso and her team discovered they’re no good at leaving the bloodstream, getting trapped instead by red blood cells.

In all vessels other than capillaries, the red cells in flowing blood tend to come together in the center. “The red blood cells sweep those particles that are less than one micron in diameter and sandwich them,” said Eniola-Adefeso. Trapped among the red cells, the nanoparticles can’t reach the vessel wall to treat disease in the blood vessels or the tissue beyond.

With their recent work, including a study recently published in the journal Langmuir, her team has shown that nanoparticle spheres face this problem in tiny arterioles and venules – one step up from capillaries – all the way up to centimeter-sized arteries. They discovered this with the help of plastic channels lined with the same cells that make up the interiors of blood vessels. Human blood, with added nano- or microspheres, ran through the channels, and the team observed whether or not the spheres migrated to the channel walls and bound themselves to the lining. With the help of confocal microscopy imaging, they present the first visual evidence that few nanospheres make it to the vessel wall in blood flow.

Namdee prepares syringes

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Katawut Namdee, a chemical engineering graduate student in Eniola-Adefeso's lab, prepares syringes for handling blood and test particles. Photo: Joseph Xu, Michigan Engineering Communications and Marketing. All rights reserved.

Mixing blood and particles

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Namdee mixes blood with test particles. Photo: Joseph Xu, Michigan Engineering Communications and Marketing. All rights reserved.

Into the model blood vessels

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Namdee runs the particle-infused blood through the model blood vessels in the microfluidic system under a microscope. Photo: Joseph Xu, Michigan Engineering Communications and Marketing. All rights reserved.

Illuminating drug carrier particles

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The particles are fluorescent under blue light, so this lighting makes them glow in the darkened room. Photo: Joseph Xu, Michigan Engineering Communications and Marketing. All rights reserved.

Through the microscope

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Alex Thompson, a chemical engineering graduate student in Eniola-Adefeso's lab, views the blood flowing through the model vessel system through a microscope. Photo: Joseph Xu, Michigan Engineering Communications and Marketing. All rights reserved.

Microspheres and cells

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Thompson views microspheres (white spots) sticking to the cells that line blood vessel walls (dark spots). Photo: Joseph Xu, Michigan Engineering Communications and Marketing. All rights reserved.

“Prior to the work that we have done, people were operating under the assumption that particles will interact with the blood vessel at some point,” said Eniola-Adefeso.

While a relatively small fraction of nanospheres filter out to the blood vessel walls, many more stay in the bloodstream and travel all over the body. Increasing the nanoparticle dose gives poor returns; after the team added five times more nanospheres to the blood samples, the number of spheres that bonded with the blood vessel lining only doubled.

“If localized drug delivery is an important goal, then nanospheres will fail,” she said.

But it’s not all bad news. The red blood cells tended to push microspheres with diameters of two microns or more toward the wall. Whether the blood flowed evenly, as it does in arterioles and venules, or in pulses, as occurs in arteries, the larger microspheres were able to reach the vessel wall and bind to it. When the team added more microspheres to the flow, they saw a proportional increase in microspheres on the vessel wall.

PhD student Katawut Namdee at work in the Cell Adhesion and Drug Delivery laboratory.

While microspheres are too large to serve as drug carriers on their own, the team suggested that microspheres could ferry nanospheres to the vessel wall, releasing them upon attachment. But the simpler approach may be nanoparticles of different shapes, which might escape the red blood cells on their own.

At present, Eniola-Adefeso and her team are experimenting with rod-shaped nanoparticles. “A sphere has no drift,” she explained, so nanospheres won’t naturally move sideways out of the red cell flow. “When a rod is flowing, it drifts, and that drift moves it closer to the vessel wall.”

The related paper titled “Margination Propensity of Vascular-Targeted Spheres from Blood Flow in a Microfluidic Model of Human Microvessels” was published online on January 30th. DOI: 10.1021/la304746p

The work is funded by the American Heart Association and the National Science Foundation.

Article topics: Drug Delivery


About Michigan Engineering: The University of Michigan College of Engineering is one of the top engineering schools in the country. Eight academic departments are ranked in the nation's top 10 -- some twice for different programs. Its research budget is one of the largest of any public university. Its faculty and students are making a difference at the frontiers of fields as diverse as nanotechnology, sustainability, healthcare, national security and robotics. They are involved in spacecraft missions across the solar system, and have developed partnerships with automotive industry leaders to transform transportation. Its entrepreneurial culture encourages faculty and students alike to move their innovations beyond the laboratory and into the real world to benefit society. Its alumni base of nearly 70,000 spans the globe.

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