Why Carbon Nanotubes Spell Trouble For Cells

It's been long known that asbestos spells trouble for human cells. Scientists have seen cells stabbed with spiky, long asbestos fibers, and the image is gory: Part of the fiber is protruding from the cell, like a quivering arrow that's found its mark.

But scientists had been unable to understand why cells would be interested in asbestos fibers and other materials at the nanoscale that are too long to be fully ingested. Now a group of researchers at Brown University explains what happens. Through molecular simulations and experiments, the team reports in Nature Nanotechnology that certain nanomaterials, such as carbon nanotubes, enter cells tip-first and almost always at a 90-degree angle. The orientation ends up fooling the cell; by taking in the rounded tip first, the cell mistakes the particle for a sphere, rather than a long cylinder. By the time the cell realizes the material is too long to be fully ingested, it's too late.

"It's as if we would eat a lollipop that's longer than us," said Huajian Gao, professor of engineering at Brown and the paper's corresponding author. "It would get stuck."

The research is important because nanomaterials like carbon nanotubes have promise in medicine, such as acting as vehicles to transport drugs to specific cells or to specific locations in the human body. If scientists can fully understand how nanomaterials interact with cells, then they can conceivably design products that help cells rather than harm them.

"If we can fully understand (nanomaterial-cell dynamics), we can make other tubes that can control how cells interact with nanomaterials and not be toxic," Gao said. "We ultimately want to stop the attraction between the nanotip and the cell."

Like asbestos fibers, commercially available carbon nanotubes and gold nanowires have rounded tips that often range from 10 to 100 nanometers in diameter. Size is important here; the diameter fits well within the cell's parameters for what it can handle. Brushing up against the nanotube, special proteins called receptors on the cell spring into action, clustering and bending the membrane wall to wrap the cell around the nanotube tip in a sequence that the authors call "tip recognition." As this occurs, the nanotube is tipped to a 90-degree angle, which reduces the amount of energy needed for the cell to engulf the particle.

Once the engulfing - endocytosis - begins, there is no turning back. Within minutes, the cell senses it can't fully engulf the nanostructure and essentially dials 911. "At this stage, it's too late," Gao said. "It's in trouble and calls for help, triggering an immune response that can cause repeated inflammation."

The team hypothesized the interaction using coarse-grained molecular dynamic simulations and capped multiwalled carbon nanotubes. In experiments involving nanotubes and gold nanowires and mouse liver cells and human mesothelial cells, the nanomaterials entered the cells tip-first and at a 90-degree angle about 90 percent of the time, the researchers report.

"We thought the tube was going to lie on the cell membrane to obtain more binding sites. However, our simulations revealed the tube steadily rotating to a high-entry degree, with its tip being fully wrapped," said Xinghua Shi, first author on the paper who earned his doctorate at Brown and is at the Chinese Academy of Sciences in Beijing. "It is counter-intuitive and is mainly due to the bending energy release as the membrane is wrapping the tube."

The team would like to study whether nanotubes without rounded tips - or less rigid nanomaterials such as nanoribbons - pose the same dilemma for cells.

"Interestingly, if the rounded tip of a carbon nanotube is cut off (meaning the tube is open and hollow), the tube lies on the cell membrane, instead of entering the cell at a high-degree-angle," Shi said.

Agnes Kane, professor of pathology and laboratory medicine at Brown, is a corresponding author on the paper. Other authors include Annette von dem Bussche from the Department of Pathology and Laboratory Medicine at Brown and Robert Hurt from the Institute for Molecular and Nanoscale Innovation at Brown.

The National Science Foundation, the U.S. Department of Commerce National Institute of Standards and Technology, the National Institute of Environmental Health Sciences Superfund Research Program, and the American Recovery and Reinvestment Act funded the research.

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How Carbon Nanotubes Can Affect Lining Of The Lungs

ScienceDaily (Oct. 25, 2009) — Carbon nanotubes are being considered for use in everything from sports equipment to medical applications, but a great deal remains unknown about whether these materials cause respiratory or other health problems. Now a collaborative study from North Carolina State University, The Hamner Institutes for Health Sciences, and the National Institute of Environmental Health Sciences shows that inhaling these nanotubes can affect the outer lining of the lung, though the effects of long-term exposure remain unclear.
See Also:Health & MedicineMesotheliomaDiseases and ConditionsChronic IllnessMatter & EnergyGrapheneNanotechnologyWeapons TechnologyReferenceMesotheliomaNanowireCarbon nanotubePulmonary alveolus
Using mice in an animal model study, the researchers set out to determine what happens when multi-walled carbon nanotubes are inhaled. Specifically, researchers wanted to determine whether the nanotubes would be able to reach the pleura, which is the tissue that lines the outside of the lungs and is affected by exposure to certain types of asbestos fibers which cause the cancer mesothelioma. The researchers used inhalation exposure and found that inhaled nanotubes do reach the pleura and cause health effects.
Short-term studies described in the paper do not allow conclusions about long-term responses such as cancer. However, the inhaled nanotubes "clearly reach the target tissue for mesothelioma and cause a unique pathologic reaction on the surface of the pleura, and caused fibrosis," says Dr. James Bonner, associate professor of environmental and molecular toxicology at NC State and senior author of the study. The "unique reaction" began within one day of inhalation of the nanotubes, when clusters of immune cells (lymphocytes and monocytes) began collecting on the surface of the pleura. Localized fibrosis, or scarring on parts of the pleural surface that is also found with asbestos exposure, began two weeks after inhalation.
The study showed the immune response and fibrosis disappeared within three months of exposure. However, this study used only a single exposure to the nanotubes. "It remains unclear whether the pleura could recover from chronic, or repeated, exposures," Bonner says. "More work needs to be done in that area and it is completely unknown at this point whether inhaled carbon nanotubes will prove to be carcinogenic in the lungs or in the pleural lining."
The mice received a single inhalation exposure of six hours as part of the study, and the effects on the pleura were only evident at the highest dose used by the researchers -- 30 milligrams per cubic meter (mg/m3). The researchers found no health effects in the mice exposed to the lower dose of one mg/m3.
The study, "Inhaled Carbon Nanotubes Reach the Sub-Pleural Tissue in Mice," was co-authored by Bonner, Dr. Jessica Ryman-Rasmussen, Dr. Arnold Brody, and Dr. Jeanette Shipley-Phillips of NC State, Dr. Jeffrey Everitt who is an adjunct faculty at NC State, Dr. Mark Cesta of the National Institute of Environmental Health Sciences (NIEHS), Earl Tewksbury, Dr. Owen Moss, Dr. Brian Wong, Dr. Darol Dodd and Dr. Melvin Andersen of The Hamner Institutes for Health Sciences. The study is published in the Oct. 25 issue of Nature Nanotechnology and was funded by The Hamner Institutes for Health Sciences, NIEHS and NC State's College of Agriculture and Life Sciences.
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