Tag Archives: Francesco Stellacci

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

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?

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.

There once was a champion … it was nano-rust

Swiss and Israeli scientists have discovered water and nano iron oxide (rust) can be used to produce solar hydrogen cheaply. From the July 7, 2013 news release on EurekAlert,

In the quest for the production of renewable and clean energy, photoelectrochemical cells (PECs) constitute a sort of a Holy Grail. PECs are devices able of splitting water molecules into hydrogen and oxygen in a single operation, thanks to solar radiation. “As a matter of fact, we’ve already discovered this precious chalice, says Michael Grätzel, Director of the Laboratory of Photonics and Interfaces (LPI) at EPFL [Ecole Polytechnique Fédérale de Lausanne] and inventor of dye-sensitized photoelectrochemical cells. Today we have just reached an important milestone on the path that will lead us forward to profitable industrial applications.”

This week, Nature Materials is indeed publishing a groundbreaking article on the subject. EPFL researchers, working with Avner Rotschild from Technion (Israel), have managed to accurately characterize the iron oxide nanostructures to be used in order to produce hydrogen at the lowest possible cost. “The whole point of our approach is to use an exceptionally abundant, stable and cheap material: rust,” adds Scott C. Warren, first author of the article.

The EFFL July 9, 2013 news release by Emmanuel Barraud about this research provides more details,

At the end of last year, Kevin Sivula, one of the collaborators at the LPI laboratory, presented a prototype electrode based on the same principle. Its efficiency was such that gas bubbles emerged as soon as it was under a light stimulus. Without a doubt, the potential of such cheap electrodes was demonstrated, even if there was still room for improvement.

By using transmission electron microscopy (TEM) techniques, researchers were able to precisely characterize the movement of the electrons through the cauliflower-looking nanostructures forming the iron oxide particles, laid on electrodes during the manufacturing process. “These measures have helped us understand the reason why we get performance differences depending on the electrodes manufacturing process”, says Grätzel.

By comparing several electrodes, whose manufacturing method is now mastered, scientists were able to identify the “champion” structure. A 10×10 cm prototype has been produced and its effectiveness is in line with expectations. The next step will be the development of the industrial process to large-scale manufacturing. A European funding and the Swiss federal government could provide support for this last part.

Evidently, the long-term goal is to produce hydrogen – the fuel of the future – in an environmentally friendly and especially competitive way. For Michael Grätzel, “current methods, in which a conventional photovoltaic cell is coupled to an electrolyzer for producing hydrogen, cost 15 € per kilo at their cheapest. We’re aiming at a € 5 charge per kilo”.

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

Identifying champion nanostructures for solar water-splitting by Scott C. Warren, Kislon Voïtchovsky, Hen Dotan, Celine M. Leroy, Maurin Cornuz, Francesco Stellacci, Cécile Hébert, Avner Rothschild & Michael Grätzel. Nature Materials (2013) doi:10.1038/nmat3684
Published online 07 July 2013

This paper is behind a paywall.

Test your tuna for mercury and other heavy metals with nano-velcro

Scientists Francesco Stellacci at the École Polytechnique Fédérale de Lausanne (EPFL) and Bartosz Grzybowski at Northwestern University have devised an easy and economical way to test for mercury and other heavy metals in fish. From the Sept. 9, 2012 news release on EurekAlert,

Mercury, when dumped in lakes and rivers, accumulates in fish, and often ends up on our plates. A Swiss-American team of researchers led by Francesco Stellacci at the Ecole Polytechnique Fédérale de Lausanne (EPFL) and Bartosz Grzybowski at Northwestern University has devised a simple, inexpensive system based on nanoparticles, a kind of nano-velcro, to detect and trap this toxic pollutant as well as others. The particles are covered with tiny hairs that can grab onto toxic heavy metals such as mercury and cadmium. This technology makes it possible to easily and inexpensively test for these substances in water and, more importantly, in the fish that we eat. Their new method can measure methyl mercury, the most common form of mercury pollution, at unprecedentedly small attomolar concentrations.

Here’s a description of how the technique works, from the Sept. 12, 2012 news release on the EPFL website,

The technology developed by the Swiss-American team is simple to use. A strip of glass covered with a film of “hairy”nanoparticles is dipped into the water. When an ion – a positively charged particle, such as a methyl mercury or cadmium ion – gets in between two hairs, the hairs close up, trapping the pollutant.

A voltage-measuring device reveals the result; the more ions there are trapped in the nano-velcro, the more electricity it will conduct. So to calculate the number of trapped particles, all one needs to do is measure the voltage across the nanostructure.

By varying the length of the nano-hairs, the scientists can target a particular kind of pollutant. “The procedure is empirical,” explains Stellacci. Methyl mercury, fortunately, has properties that make it extremely easy to trap without accidentally trapping other substances at the same time; thus the results are very reliable.

The interesting aspect of this approach is that the ‘reading’ glass strip could costs less than 10 dollars, while the measurement device will cost only a few hundreds of dollars. The analysis can be done in the field, so the results are immediately available. “With a conventional method, you have to send samples to the laboratory, and the analysis equipment costs several million dollars,” notes Stellacci.

They have tested the system in the field,

The researchers tested the system in Lake Michigan, near Chicago. Despite the high level of industry in the region, mercury levels were extremely low. “The goal was to compare our measurements to FDA [US Food and Drug Administration] measurements done using conventional methods,” explains Stellacci. “Our results fell within an acceptable range.”

A mosquito fish from the Everglades in Florida was also tested. This species is not very high on the food chain and thus does not accumulate high levels of mercury in its tissues. “We measured tissue that had been dissolved in acid. The goal was to see if we could detect even minuscule quantities.” says Bartosz Grzybowski, Burgess Professor of Chemistry and Director of Non-Equilibrium Energy Research Center at Northwestern University. The United States Geological Survey reported near-identical results after analyzing the same sample.

“I think it is quite incredible,” Grzybowski adds, “how the complex principles of quantum tunneling underlying our device translate into such an accurate and practically useful device. It is also notable that our system – through some relatively simple chemical modifications – can be readily adapted to detect other toxic species” Researchers have already demonstrated the detection of cadmium with a very high femtomolar sensitivity.

“With this technology, it will be possible to conduct tests on a much larger scale in the field, or even in fish before they are put on the market,” says lead author Eun Seon Cho. This is a necessary public health measure, given the toxic nature of methyl mercury and the extremely complex manner in which it spreads in the environment and accumulates in living tissues.

Northwestern University provided an illustration of the nano-velcro trapping an ion of heavy metal,

Nano-velcro (Courtesy Northwestern University & EPFL; downloaded from http://actu.epfl.ch/news/nano-velcro-clasps-heavy-metal-molecules-in-its-gr/)