Tag Archives: Alfredo Alexander-Katz

New kind of long-range particle interactions found by Massachusetts Institute of Technology (MIT) team

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A team from the Massachusetts Institute of Technology (MIT) found unexpected long-range interactions amongst particles in a liquid medium according to an April 12, 2016 news item on ScienceDaily,

Moving bodies can be attracted to each other, even when they’re quite far apart and separated by many other objects: That, in a nutshell, is the somewhat unexpected finding by a team of researchers at MIT.

Scientists have known for a long time that small particles of matter, from the size of dust to sand grains, can exert influences on each other through electrical, magnetic, or chemical effects. Now, this team has found a new kind of long-range interaction between particles, in a liquid medium, that is based entirely on their motions. And these interactions should apply to any kind of particles that move, whether they be living cells or metal particles whirled by magnetic fields.

An April 11, 2016 MIT news release (also on EurekAlert), which originated the news item, describes the work in more detail,

The discovery, which holds for both living and nonliving particles, is described in a paper by Alfredo Alexander-Katz, the Walter Henry Gale Associate Professor of Materials Science and Engineering at MIT, and his co-researchers, in the Proceedings of the National Academies of Sciences.

Alexander-Katz describes the kind of interactions his team found as being related to the research field of active matter. Example of active systems are the flocking behavior of birds or the schooling of fish. Each individual member of the system may be responding just to others in its vicinity, but the result is a coherent overall pattern of movement that can span a large region. Cells in a fluid medium, or even tiny structures moving within a cell, exhibit similar kinds of motion, he says.

The researchers studied magnetic particles a few micrometers (millionths of a meter) across, comparable to the size of some cells. A small number of these magnetic metal microparticles were interspersed with a much larger quantity of inert particles of comparable size, all suspended in water. When a rotating magnetic field was applied, the metal particles would begin to spin, simulating the movements of living cells in the midst of nonliving or relatively inert objects — such as when cells migrate through tissues or move in a crowded environment.

They found that the spinning particles, even when separated by distances tens of times their size, would ultimately migrate toward each other. Though that attraction progressed through a slow and apparently random series of motions, the particles would in the end almost always come together.

While there has been a lot of research on interactions among active particles, Alexander-Katz says, this is one of the few studies that has looked at the way such particles interact when they are surrounded by inactive particles. “In the absence of the inactive particles there are essentially no interactions,” he says.

The unexpected finding might ultimately lead to a better understanding of the behavior of some natural biological systems or new methods for creating synthetic active materials which could be useful for selectively delivering drugs into certain parts of the body, Alexander-Katz suggests. It could also end up finding applications in electronics or energy-harvesting systems, for example providing a way to flip a crystal structure between two different configurations.

“What we’re addressing is collective excitations of the system, or coherent excitations,” he explains. “What we’re looking at is, what are the interactions as a function of activity” of the individual particles.

The faster the particles spin, the greater the attraction between them, the team found. Below a certain speed the effect stops altogether. But the amount of inert matter also makes a difference, they found.

With no inert particles — if the moving particles are suspended in clear water — there is no motion-based attraction. But when the nonspinning particles are added and their concentration reaches a certain point, “there is attraction!” Alexander-Katz says.

One unexpected aspect of the findings was how far the effect extended. “What was really surprising was that the range of the interactions is gigantic,” he says. By way of comparison, he says, imagine you’re in a crowd, and you start to move a bit, and someone else also starts to move, while everyone else tries to stand still. “I would be able to sense, even 20 people away or more, that that person is also active — assuming that the other folks around us are not active.”

The attraction, he says, “is not chemical, it is not magnetic, it is not electrostatic, it’s just based on activity.” And because the range is so long, these interactions could not be modeled in simulations but required physical experiments to be uncovered. The tests by Alexander-Katz and his team used two-dimensional films, similar to particle sediments that form on a rock surface, he says.

He speculates that some biological organisms may use this phenomenon as a way of sensing parts of their environment, though this has not yet been tested.

There is an MIT video illustrating the work,

Here’s a link to and a citation for the paper,

Emergent ultra–long-range interactions between active particles in hybrid active–inactive systems by Joshua P. Steimel, Juan L. Aragones, Helen Hu, Naser Qureshi, and Alfredo Alexander-Katz. Proceedings of the National Academy of Sciences,  2016; 201520481 doi: 10.1073/pnas.1520481113

This paper is behind a paywall.

Gold on the brain, a possible nanoparticle delivery system for drugs

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A July 21, 2014 news item on Nanowerk describes special gold nanoparticles that could make drug delivery to cells easier,

A special class of tiny gold particles can easily slip through cell membranes, making them good candidates to deliver drugs directly to target cells.

A new study from MIT materials scientists reveals that these nanoparticles enter cells by taking advantage of a route normally used in vesicle-vesicle fusion, a crucial process that allows signal transmission between neurons.

A July 21, 2014 MIT (Massachusetts Institute of Technology) news release (also on EurekAlert), which originated the news item, provides more details,

The findings suggest possible strategies for designing nanoparticles — made from gold or other materials — that could get into cells even more easily.

“We’ve identified a type of mechanism that might be more prevalent than is currently known,” says Reid Van Lehn, an MIT graduate student in materials science and engineering and one of the paper’s lead authors. “By identifying this pathway for the first time it also suggests not only how to engineer this particular class of nanoparticles, but that this pathway might be active in other systems as well.”

The paper’s other lead author is Maria Ricci of École Polytechnique Fédérale de Lausanne (EPFL) in Switzerland. The research team, led by Alfredo Alexander-Katz, an associate professor of materials science and engineering, and Francesco Stellacci from EPFL, also included scientists from the Carlos Besta Institute of Neurology in Italy and Durham University in the United Kingdom.

Most nanoparticles enter cells through endocytosis, a process that traps the particles in intracellular compartments, which can damage the cell membrane and cause cell contents to leak out. However, in 2008, Stellacci, who was then at MIT, and Darrell Irvine, a professor of materials science and engineering and of biological engineering, found that a special class of gold nanoparticles coated with a mix of molecules could enter cells without any disruption.

“Why this was happening, or how this was happening, was a complete mystery,” Van Lehn says.

Last year, Alexander-Katz, Van Lehn, Stellacci, and others discovered that the particles were somehow fusing with cell membranes and being absorbed into the cells. In their new study, they created detailed atomistic simulations to model how this happens, and performed experiments that confirmed the model’s predictions.

Gold nanoparticles used for drug delivery are usually coated with a thin layer of molecules that help tune their chemical properties. Some of these molecules, or ligands, are negatively charged and hydrophilic, while the rest are hydrophobic. The researchers found that the particles’ ability to enter cells depends on interactions between hydrophobic ligands and lipids found in the cell membrane.

Cell membranes consist of a double layer of phospholipid molecules, which have hydrophobic lipid tails and hydrophilic heads. The lipid tails face in toward each other, while the hydrophilic heads face out.

In their computer simulations, the researchers first created what they call a “perfect bilayer,” in which all of the lipid tails stay in place within the membrane. Under these conditions, the researchers found that the gold nanoparticles could not fuse with the cell membrane.

However, if the model membrane includes a “defect” — an opening through which lipid tails can slip out — nanoparticles begin to enter the membrane. When these lipid protrusions occur, the lipids and particles cling to each other because they are both hydrophobic, and the particles are engulfed by the membrane without damaging it.

In real cell membranes, these protrusions occur randomly, especially near sites where proteins are embedded in the membrane. They also occur more often in curved sections of membrane, because it’s harder for the hydrophilic heads to fully cover a curved area than a flat one, leaving gaps for the lipid tails to protrude.

“It’s a packing problem,” Alexander-Katz says. “There’s open space where tails can come out, and there will be water contact. It just makes it 100 times more probable to have one of these protrusions come out in highly curved regions of the membrane.”

This phenomenon appears to mimic a process that occurs naturally in cells — the fusion of vesicles with the cell membrane. Vesicles are small spheres of membrane-like material that carry cargo such as neurotransmitters or hormones.

The similarity between absorption of vesicles and nanoparticle entry suggests that cells where a lot of vesicle fusion naturally occurs could be good targets for drug delivery by gold nanoparticles. The researchers plan to further analyze how the composition of the membranes and the proteins embedded in them influence the absorption process in different cell types. “We want to really understand all the constraints and determine how we can best design nanoparticles to target particular cell types, or regions of a cell,” Van Lehn says.

Here’s a link to and a citation for the paper,

Lipid tail protrusions mediate the insertion of nanoparticles into model cell membranes by Reid C. Van Lehn, Maria Ricci, Paulo H.J. Silva, Patrizia Andreozzi, Javier Reguera, Kislon Voïtchovsky, Francesco Stellacci, & Alfredo Alexander-Katz. Nature Communications 5, Article number: 4482 doi:10.1038/ncomms5482 Published 21 July 2014

This article is behind a paywall but there is a free preview available via ReadCube Access.

I last featured this multi-country team’s work on gold nanoparticles in an Aug. 23, 2013 posting.

So, why do gold nanoparticles facilitate cell penetration without damage to cell walls?

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Researchers at the Massachusetts Institute of Technology (MIT) and l’École Polytechnique Fédérale de Lausanne (EPFL) in Switerzerland have found an answer to the question about why gold nanoparticles facilitate cell penetration without damage to the cell walls. Apparently it has nothing to with the gold; it’s all in the coating according to an Aug. 23, 2013 MIT news release by David L. Chandler (also on EurekAlert),

Cells are very good at protecting their precious contents — and as a result, it’s very difficult to penetrate their membrane walls to deliver drugs, nutrients or biosensors without damaging or destroying the cell. One effective way of doing so, discovered in 2008, is to use nanoparticles of pure gold, coated with a thin layer of a special polymer. But nobody knew exactly why this combination worked so well, or how it made it through the cell wall.

Now, researchers at MIT and the Ecole Polytechnique de Lausanne in Switzerland have figured out how the process works, and the limits on the sizes of particles that can be used. …

Until now, says Van Lehn, the paper’s lead author [Reid Van Lehn], “the mechanism was unknown. … In this work, we wanted to simplify the process and understand the forces” that allow gold nanoparticles to penetrate cell walls without permanently damaging the membranes or rupturing the cells. The researchers did so through a combination of lab experiments and computer simulations.

The news release goes on to provide details about the research,

The team demonstrated that the crucial first step in the process is for coated gold nanoparticles to fuse with the lipids — a category of natural fats, waxes and vitamins — that form the cell wall. The scientists also demonstrated an upper limit on the size of such particles that can penetrate the cell wall — a limit that depends on the composition of the particle’s coating. [emphases mine]

The coating applied to the gold particles consists of a mix of hydrophobic and hydrophilic components that form a monolayer — a layer just one molecule thick — on the particle’s surface. Any of several different compounds can be used, the researchers explain. [emphases mine]

“Cells tend to engulf things on the surface,” says Alexander-Katz, an associate professor of materials science and engineering at MIT, but it’s “very unusual” for materials to cross that membrane into the cell’s interior without causing major damage. Irvine and Stellacci demonstrated in 2008 that monolayer-coated gold nanoparticles could do so; they have since been working to better understand why and how that works.

Since the nanoparticles themselves are completely coated, the fact that they are made of gold doesn’t have any direct effect, except that gold nanoparticles are an easily prepared model system, the researchers say. However, there is some evidence that the gold particles have therapeutic properties, which could be a side benefit.

Gold particles are also very good at capturing X-rays — so if they could be made to penetrate cancer cells, and were then heated by a beam of X-rays, they could destroy those cells from within. “So the fact that it’s gold may be useful,” says Irvine, a professor of materials science and engineering and biological engineering and member of the Koch Institute for Integrative Cancer Research.

Significantly, the mechanism that allows the nanoparticles to pass through the membrane seems also to seal the opening as soon as the particle has passed. “They would go through without allowing even small molecules to leak through behind them,” Van Lehn says.

Irvine says that his lab is also interested in harnessing this cell-penetrating mechanism as a way of delivering drugs to the cell’s interior, by binding them to the surface coating material. One important step in making that a useful process, he says, is finding ways to allow the nanoparticle coatings to be selective about what types of cells they attach to. “If it’s all cells, that’s not very useful,” he says, but if the coatings can be targeted to a particular cell type that is the target of a drug, that could be a significant benefit.

Another potential application of this work could be in attaching or inserting biosensing molecules on or into certain cells, Van Lehn says. In this way, scientists could detect or monitor specific biochemical markers, such as proteins that indicate the onset or decline of a disease or a metabolic process.

The research paper can be found here,

Effect of Particle Diameter and Surface Composition on the Spontaneous Fusion of Monolayer-Protected Gold Nanoparticles with Lipid Bilayers by Reid C. Van Lehn, Prabhani U. Atukorale, Randy P. Carney, Yu-Sang Yang, Francesco Stellacci, Darrell J. Irvine, and Alfredo Alexander-Katz. Nano Lett., Article ASAP DOI: 10.1021/nl401365n Publication Date (Web): August 5, 2013
Copyright © 2013 American Chemical Society

It is behind a paywall.