Self-assembling nanoparticle arrays can switch between a mirror and a window

By finely tuning the distance between nanoparticles in a single layer, researchers have made a filter that can change between a mirror and a window.

The development could help scientists create special materials whose optical properties can be changed in real time. These materials could then be used for applications from tuneable optical filters to miniature chemical sensors.

Creating a 'tuneable' material - one which can be accurately controlled - has been a challenge because of the tiny scales involved. In order to tune the optical properties of a single layer of nanoparticles - which are only tens of nanometres in size each - the space between them needs to be set precisely and uniformly.

To form the layer, the team of researchers from Imperial College London created conditions for gold nanoparticles to localise at the interface between two liquids that do not mix. By applying a small voltage across the interface, the team have been able to demonstrate a tuneable nanoparticle layer that can be dense or sparse, allowing for switching between a reflective mirror and a transparent surface. The research is published today in Nature Materials.

Study co-author Professor Joshua Edel, from the Department of Chemistry at Imperial, said: "It's a really fine balance - for a long time we could only get the nanoparticles to clump together when they assembled, rather than being accurately spaced out. But many models and experiments have brought us to the point where we can create a truly tuneable layer."

The distance between the nanoparticles determines whether the layer permits or reflects different wavelengths of light. At one extreme, all the wavelengths are reflected, and the layer acts as a mirror. At the other extreme, where the nanoparticles are dispersed, all wavelengths are permitted through the interface and it acts as a window.

In contrast to previous nanoscopic systems that used chemical means to change the optical properties, the team's electrical system is reversible.

Study co-author Professor Alexei Kornyshev, from the Department of Chemistry at Imperial, said: "Finding the correct conditions to achieve reversibility required fine theory; otherwise it would have been like searching for a needle in a haystack. It was remarkable how closely the theory matched experimental results."

Co-author Professor Anthony Kucernak, also from the Department of Chemistry, commented: "Putting theory into practice can be difficult, as one always has to be aware of material stability limits, so finding the correct electrochemical conditions under which the effect could occur was challenging."

Professor Kornyshev added: "The whole project was only made possible by the unique knowhow and abilities and enthusiasm of the young team members, including Dr Yunuen Montelongo and Dr Debarata Sikdar, amongst others who all have diverse expertise and backgrounds."

Electrotunable nanoplasmonic liquid mirror
Yunuen Montelongo, Debabrata Sikdar, Ye Ma, Alastair J. S. McIntosh, Leonora Velleman, Anthony R. Kucernak,    Joshua B. Edel & Alexei A. Kornyshev
Nature Materials (2017) doi:10.1038/nmat4969

Imperial College London

A ‘printing press’ for nanoparticles

This new technique could facilitate use of gold nanoparticles in electronic, medical applications

Gold nanoparticles have unusual optical, electronic and chemical properties, which scientists are seeking to put to use in a range of new technologies, from nanoelectronics to cancer treatments.

Some of the most interesting properties of nanoparticles emerge when they are brought close together – either in clusters of just a few particles or in crystals made up of millions of them.  Yet particles that are just millionths of an inch in size are too small to be manipulated by conventional lab tools, so a major challenge has been finding ways to assemble these bits of gold while controlling the three-dimensional shape of their arrangement.

One approach that researchers have developed has been to use tiny structures made from synthetic strands of DNA to help organize nanoparticles. Since DNA strands are programmed to pair with other strands in certain patterns, scientists have attached individual strands of DNA to gold particle surfaces to create a variety of assemblies. But these hybrid gold-DNA nanostructures are intricate and expensive to generate, limiting their potential for use in practical materials. The process is similar, in a sense, to producing books by hand.

Enter the nanoparticle equivalent of the printing press. It’s efficient, re-usable and carries more information than previously possible. In results reported online in Nature Chemistry, researchers from McGill’s Department of Chemistry outline a procedure for making a DNA structure with a specific pattern of strands coming out of it; at the end of each strand is a chemical “sticky patch.”  When a gold nanoparticle is brought into contact to the DNA nanostructure, it sticks to the patches. The scientists then dissolve the assembly in distilled water, separating the DNA nanostructure into its component strands and leaving behind the DNA imprint on the gold nanoparticle. (See illustration.)

“These encoded gold nanoparticles are unprecedented in their information content,” says senior author Hanadi Sleiman, who holds the Canada Research Chair in DNA Nanoscience. “The DNA nanostructures, for their part, can be re-used, much like stamps in an old printing press.”

From stained glass to optoelectronics

Some of the properties of gold nanoparticles have been recognized for centuries.  Medieval artisans added gold chloride to molten glass to create the ruby-red colour in stained-glass windows – the result, as chemists figured out much later, of the light-scattering properties of tiny gold particles. 

Now, the McGill researchers hope their new production technique will help pave the way for use of DNA-encoded nanoparticles in a range of cutting-edge technologies. First author Thomas Edwardson says the next step for the lab will be to investigate the properties of structures made from these new building blocks. “In much the same way that atoms combine to form complex molecules, patterned DNA gold particles can connect to neighbouring particles to form well-defined nanoparticle assemblies.”

These could be put to use in areas including optoelectronic nanodevices and biomedical sciences, the researchers say. The patterns of DNA strands could, for example, be engineered to target specific proteins on cancer cells, and thus serve to detect cancer or to selectively destroy cancer cells. 

Financial support for the research was provided by the Natural Sciences and Engineering Research Council of Canada, the Canada Foundation for Innovation, the Centre for Self-Assembled Chemical Structures, the Canada Research Chairs Program and the Canadian Institutes of Health Research.

“Transfer of molecular recognition information from DNA nanostructures to gold nanoparticles,” Thomas G. W. Edwardson et al, Nature Chemistry, Jan. 4, 2016. DOI: 10.1038/nchem.2420
http://www.nature.com/nchem/journal/vaop/ncurrent/full/nchem.2420.html

McGill University

Electric Fields Remove Nanoparticles From Blood With Ease

Engineers at the University of California, San Diego developed a new technology that uses an oscillating electric field to easily and quickly isolate drug-delivery nanoparticles from blood. The technology could serve as a general tool to separate and recover nanoparticles from other complex fluids for medical, environmental, and industrial applications.

Nanoparticles, which are generally one thousand times smaller than the width of a human hair, are difficult to separate from plasma, the liquid component of blood, due to their small size and low density. Traditional methods to remove nanoparticles from plasma samples typically involve diluting the plasma, adding a high concentration sugar solution to the plasma and spinning it in a centrifuge, or attaching a targeting agent to the surface of the nanoparticles. These methods either alter the normal behavior of the nanoparticles or cannot be applied to some of the most common nanoparticle types.

“This is the first example of isolating a wide range of nanoparticles out of plasma with a minimum amount of manipulation,” said Stuart Ibsen, a postdoctoral fellow in the Department of NanoEngineering at UC San Diego and first author of the study published October in the journal Small. “We’ve designed a very versatile technique that can be used to recover nanoparticles in a lot of different processes.”

This new nanoparticle separation technology will enable researchers — particularly those who design and study drug-delivery nanoparticles for disease therapies — to better monitor what happens to nanoparticles circulating in a patient’s bloodstream. One of the questions that researchers face is how blood proteins bind to the surfaces of drug-delivery nanoparticles and make them less effective. Researchers could also use this technology in the clinic to determine if the blood chemistry of a particular patient is compatible with the surfaces of certain drug-delivery nanoparticles.

“We were interested in a fast and easy way to take these nanoparticles out of plasma so we could find out what’s going on at their surfaces and redesign them to work more effectively in blood,” said Michael Heller, a nanoengineering professor at the UC San Diego Jacobs School of Engineering and senior author of the study.

The device used to isolate the drug-delivery nanoparticles was a dime-sized electric chip manufactured by La Jolla-based Biological Dynamics, which licensed the original technology from UC San Diego. The chip contains hundreds of tiny electrodes that generate a rapidly oscillating electric field that selectively pulls the nanoparticles out of a plasma sample. Researchers inserted a drop of plasma spiked with nanoparticles into the electric chip and demonstrated nanoparticle recovery within 7 minutes. The technology worked on different types of drug-delivery nanoparticles that are typically studied in various labs.

The breakthrough in the technology relies on designing a chip that can work in the high salt concentration of blood plasma. The chip’s ability to pull the nanoparticles out of plasma is based on differences in the material properties between the nanoparticles and plasma components.

When the chip’s electrodes apply an oscillating electric field, the positive and negative charges inside the nanoparticles reorient themselves at a different speed than the charges in the surrounding plasma. This momentary imbalance in the charges creates an attractive force between the nanoparticles and the electrodes. As the electric field oscillates, the nanoparticles are continually pulled towards the electrodes, leaving the rest of the plasma behind. Also, the electric field is designed to oscillate at just the right frequency: 15,000 times per second.

“It’s amazing that this method works without any modifications to the plasma samples or to the nanoparticles,” said Ibsen.

UC San Diego

A New Approach to Engineering the Materials of the Future

Transmission electron microscope (TEM) images and GISAXS
paEerns (insets) of two giant surfactant thin­‐film samples.
The TEM images show ordered nanoscale paEerns.

Some of the most interesting and fascinating electronic devices that will someday be available to consumers, from paper-thin computers to electronic fabric, will be the result of advanced materials designed by scientists. Indeed, some remarkable discoveries have already been made. To innovate further, scientists must learn how to precisely engineer the chemical structures of materials at the nanoscale in such a way as to yield specific macroscopic properties and functions.

A research group, jointly working at theNational Synchrotron Light Source, has found a new way to do just that. They have synthesized a new class of macromolecules that organize themselves, or “self-assemble,” into various ordered structures with feature sizes smaller than 10 nanometers. Called “giant surfactants,” these large molecules mimic the structural features of small surfactants (substances that significantly lower the surface tension between two liquids, such as detergents), but have been transformed into functional molecular nanoparticles by being “clicked” with polymer chains. The resulting materials are unique because they bridge the gap between small molecule surfactants and traditional block copolymers and thus possess an interesting “duality” in their self-assembly behaviors.

“This class of materials provides a versatile platform for engineering nanostructures that have features smaller than 10 nanometers, which is a scale that is very relevant to the blueprints of nanotechnology and microelectronics,” said the study’s corresponding scientist Stephen Cheng, a researcher in the University of Akron’s College of Polymer Science and Polymer Engineering. “More broadly, we are also interested in how our results could help advance our understanding of the chemical and physical principles that underlie self-assembly.”

Surfactants play a huge role in our everyday life, although most people are unaware of them. They are present in household cleaners and soaps, adhesives, paint, ink, plastics, and many, many other products. Naturally, they are a key part of materials research.

Giant surfactants have the potential to be even more versatile than their smaller counterparts because they have the advantages of both a polymer and a surfactant. They are of particular interest to the electronics industry because they can spontaneously self-assemble into nanodomains just a few nanometers in size. This length scale must be achieved in order to allow the continual downsizing of computer chips but proven very difficult to achieve for conventional technologies. The production of nanopatterned thin films – which are the foundation of modern computer chips – could be directly affected by giant surfactants. If films can be produced with smaller nanoscale features, they could lead to denser, faster computer chips.

The group used several techniques to study different giant surfactant samples in thin-film form, as well as in bulk form and in solution. These techniques included grazing-incidence small-angle x-ray scattering (GISAXS) at NSLS beamline X9. GISAXS is suited to studying thin film samples that have ordered nanoscale features, typically between 5 and 20 nanometers, and can tell researchers about the shape, size, and orientation of these features, among other information. It is widely used to study self-assembled thin films with nanoscale features.

This research is published in the June 18, 2013 issue of the Proceedings of the National Academy of Sciences. The team, which includes scientists from the University of Akron, National Tsing Hua University (Taiwan), McMaster University (Canada), and Peking University (China), has also described this research in a pending patent application.

http://www.bnl.gov/newsroom/news.php?a=24808

Ordered arrays of nanoporous gold nanoparticles

SEM images (false color) at 25° tilt of the perfectly
ordered array of the nanoporous gold nanoparticles
formed from the 15 nm Au/30 nm Ag bilayers.© 2012 Wang et al; licensee Beilstein-Institut.

A combination of a “top-down” approach (substrate-conformal imprint lithography) and two “bottom-up” approaches (dewetting and dealloying) enables fabrication of perfectly ordered 2-dimensional arrays of nanoporous gold nanoparticles. 

The dewetting of Au/Ag bilayers on the periodically prepatterned substrates leads to the interdiffusion of Au and Ag and the formation of an array of Au–Ag alloy nanoparticles. The array of alloy nanoparticles is transformed into an array of nanoporous gold nanoparticles by a following dealloying step. 

Large areas of this new type of material arrangement can be realized with this technique. In addition, this technique allows for the control of particle size, particle spacing, and ligament size (or pore size) by varying the period of the structure, total metal layer thickness, and the thickness ratio of the as-deposited bilayers.

Metallic nanoparticle arrays are attracting more and more attention due to their potential applications in plasmonics, magnetic memories, DNA detection, and catalytic nanowire growth. Nanoporous gold is very interesting for application in catalysi, for sensors, for actuators, and as electrodes for electrochemical supercapacitors. This is due to the unique structural, mechanical and chemical properties of this material. Nanoporous gold, already synthesized in the form of nanoparticles, possesses a much higher surface-to-volume ratio than bulk nanoporous gold films and gold nanoparticles. These nanoporous gold nanoparticles are expected to broaden the range of applications for both gold nanoparticles and nanoporous gold due to their two-level nanostructures (porosity of around 10 nm and particle size of a few hundreds of nanometers).

Solid-state dewetting of metal films is a simple “bottom-up” approach to fabricate nanoparticles. The dewetting of metal films is driven by reducing the surface energy of the film and the interface energy between the film and the substrate, and occurs by diffusion even well below the melting temperature of the film. In addition, alloy nanoparticles can be fabricated by exploiting the dewetting of metallic bilayers. By combining both, “top-down” approaches (such as lithography) and “bottom-up” approaches, an ordered array of metallic nanoparticles can be fabricated. The surface of the substrate is prepatterned into periodic structures by using laser interference lithography, focused ion beam (FIB), or substrate conformal imprint lithography (SCIL). During the dewetting of metal films onto prepatterned substrates, the periodic structure of the prepatterned substrates modulates the local excess chemical potential by the local curvature or by limiting the diffusion paths. This leads to the formation of 2-D nanoparticle arrays with well-defined particle size and particle spacing. Dealloying is a “bottom-up” approach to fabricate nanoporous gold by selectively removing or leaching the element Ag from the Au–Ag alloy in an Ag-corrosive environment. In this paper, perfectly ordered arrays of nanoporous gold nanoparticles are fabricated by using a combination of a “top-down” approach (SCIL) and two “bottom-up” approaches (dewetting and dealloying).

Full paper: http://www.beilstein-journals.org/bjnano/single/articleFullText.htm?publicId=2190-4286-3-74

Never say never in the nano-world

Artistic impressions of the nanoparticle in a laser trap.
(Image credits: Iñaki Gonzalez and Jan Gieseler)

Objects with sizes in the nanometer range, such as the molecular building blocks of living cells or nanotechnological devices, are continuously exposed to random collisions with surrounding molecules. In such fluctuating environments the fundamental laws of thermodynamics that govern our macroscopic world need to be rewritten. 

An international team of researchers from Barcelona, Zurich and Vienna found that a nanoparticle trapped with laser light temporarily violates the famous second law of thermodynamics, something that is impossible on human time and length scale. They report about their results in the latest issue of the prestigious scientific journal Nature Nanotechnology.

Surprises at the nanoscale

Watching a movie played in reverse often makes us laugh because unexpected and mysterious things seem to happen: glass shards lying on the floor slowly start to move towards each other, magically assemble and suddenly an intact glass jumps on the table where it gently gets to a halt. Or snow starts to from a water puddle in the sun, steadily growing until an entire snowman appears as if molded by an invisible hand. When we see such scenes, we immediately realize that according to our everyday experience something is out of the ordinary. Indeed, there are many processes in nature that can never be reversed. The physical law that captures this behavior is the celebrated second law of thermodynamics, which posits that the entropy of a system – a measure for the disorder of a system – never decreases spontaneously, thus favoring disorder (high entropy) over order (low entropy).

However, when we zoom into the microscopic world of atoms and molecules, this law softens up and looses its absolute strictness. Indeed, at the nanoscale the second law can be fleetingly violated. On rare occasions, one may observe events that never happen on the macroscopic scale such as, for example heat transfer from cold to hot which is unheard of in our daily lives. Although on average the second law of thermodynamics remains valid even in nanoscale systems, scientists are intrigued by these rare events and are investigating the meaning of irreversibility at the nanoscale.

Nanoparticles in laser traps

Recently, a team of physicists of the University of Vienna, the Institute of Photonic Sciences in Barcelona and the Swiss Federal Institute of Technology in Zürich succeeded in accurately predicting the likelihood of events transiently violating the second law of thermodynamics. They immediately put the mathematical fluctuation theorem they derived to the test using a tiny glass sphere with a diameter of less than 100 nm levitated in a trap of laser light. Their experimental set-up allowed the research team to capture the nano-sphere and hold it in place, and, furthermore, to measure its position in all three spatial directions with exquisite precision. In the trap, the nano-sphere rattles around due to collisions with surrounding gas molecules. 

By a clever manipulation of the laser trap the scientists cooled the nano-sphere below the temperature of the surrounding gas and, thereby, put it into a non-equilibrium state. They then turned off the cooling and watched the particle relaxing to the higher temperature through energy transfer from the gas molecules. The researchers observed that the tiny glass sphere sometimes, although rarely, does not behave as one would expect according to the second law: the nano-sphere effectively releases heat to the hotter surroundings rather than absorbing the heat. The theory derived by the researchers to analyze the experiment confirms the emerging picture on the limitations of the second law on the nanoscale.

Nanomachines out of equilibrium

The experimental and theoretical framework presented by the international research team in the renowned scientific journal Nature Nanotechnology has a wide range of applications. Objects with sizes in the nanometer range, such as the molecular building blocks of living cells or nanotechnological devices, are continuously exposed to a random buffeting due to the thermal motion of the molecules around them. As miniaturization proceeds to smaller and smaller scales nanomachines will experience increasingly random conditions. Further studies will be carried out to illuminate the fundamental physics of nanoscale systems out of equilibrium. The planned research will be fundamental to help us understand how nanomachines perform under these fluctuating conditions.

Original publication in Nature Nanotechnology

Dynamic Relaxation of a Levitated Nanoparticle from a Non-Equilibrium Steady State. Jan Gieseler, Romain Quidant, Christoph Dellago, and Lukas Novotny. Nature Nanotechnology AOP, February 28, 2014. DOI: 10.1038/NNANO.2014.40

Source: http://medienportal.univie.ac.at//presse/aktuelle-pressemeldungen/detailansicht/artikel/never-say-never-in-the-nano-world/

New Nanoparticles Target Tumors, Release Killer Protein, Activate Immune System to Kill Cancer

One of the most promising technologies for the treatment of various cancers is nanotechnology, creating drugs that directly attack the cancer cells without damaging other tissues’ development. The Laboratory of Cellular Oncology at the Research Unit in Cell Differentiation and Cancer, of the Faculty of Higher Studies (FES) Zaragoza UNAM (National Autonomous University of Mexico) developed a therapy to attack cervical cancer tumors.

The treatment, which has been tested in animal models, consists of a nanostructured composition encapsulating a protein called interleukin-2 (IL -2), lethal to cancer cells.

According to the researcher Rosalva Rangel Corona, head of the project, the antitumor effect of interleukin in cervical cancer is because their cells express receptors for interleukin-2 that “fit together " like puzzle pieces with the protein to activate an antitumor response .

The scientist explains that the nanoparticle works as a bridge of antitumor activation between tumor cells and T lymphocytes. The nanoparticle has interleukin 2 on its surface, so when the protein is around it acts as a switch, a contact with the cancer cell to bind to the receptor and to carry out its biological action.

Furthermore, the nanoparticle concentrates interleukin 2 in the tumor site, which allows its accumulation near the tumor growth. It is not circulating in the blood stream, is “out there" in action.

The administration of IL-2 using the nanovector reduces the side effects caused by this protein if administered in large amounts to the body. These effects can be fever, low blood pressure, fluid retention and attack to the central nervous system, among others.

It is known that interleukin -2 is a protein (a cytokine, a product of the cell) generated by active T cells. The nanoparticle, the vector for IL-2, carries the substance to the receptors in cancer cells, then saturates them and kills them, besides generating an immune T cells bridge (in charge of activating the immune response of the organism). This is like a guided missile acting within tumor cells and activating the immune system cells that kill them.

A woman immunosuppressed by disease produces even less interleukin. For this reason, the use of the nanoparticle would be very beneficial for female patients.

The researcher emphasized that his group must meet the pharmaceutical regulations to carry their research beyond published studies and thus benefit the population. (Agencia ID)

http://www.unam.mx/index/en

Nanoparticles target anti-inflammatory drugs where needed

Bottom right shows green-labeled neutrophils with
red-labeled nanoparticles inside, which appear yellow

Researchers at the University of Illinois at Chicago have developed a system for precisely delivering anti-inflammatory drugs to immune cells gone out of control, while sparing their well-behaved counterparts. 

Their findings were published online Feb. 23 in Nature Nanotechnology. The system uses nanoparticles made of tiny bits of protein designed to bind to unique receptors found only on neutrophils, a type of immune cell engaged in detrimental acute and chronic inflammatory responses. 

In a normal immune response, neutrophils circulating in the blood respond to signals given off by injured or damaged blood vessels and begin to accumulate at the injury, where they engulf bacteria or debris from injured tissue that might cause infection. In chronic inflammation, neutrophils can pile up at the site of injury, sticking to the blood vessel walls and to each other and contributing to tissue damage. 

Adhesion of neutrophils to blood vessel walls is a major factor in acute lung injury, where it can impair the exchange of gases between the lungs and blood, leading to severe breathing problems. If untreated, the disease has a 50 percent mortality rate in intensive care units.

Corticosteroids and non-steroidal anti-inflammatory drugs used to treat inflammatory diseases are “blunt instruments that affect the whole body and carry some significant side effects,” says Asrar B. Malik, the Schweppe Family Distinguished Professor and head of pharmacology in the UIC College of Medicine, who is lead author of the paper. 

Neutrophils that are stuck to blood vessels or clumped together have unique receptors on their surface that circulating neutrophils lack. Malik and his colleagues designed a nanoparticle to take advantage by embedding it with an anti-inflammatory drug. 

The nanoparticles bind to the receptors, and the neutrophils internalize the nanoparticle. Once inside, the anti-inflammatory drug works to “unzip” the neutrophil and allow it to re-enter the bloodstream. “The nanoparticle is very much like a Trojan horse,” Malik said. “It binds to a receptor found only on these activated, sticky neutrophils, and the cell automatically engulfs whatever binds there. 

Because circulating neutrophils lack these receptors, the system is incredibly precise and targets only those immune cells that are actively contributing to inflammatory disease.” Malik, along with research assistant professor Zhenjia Wang and assistant professor Jaehyung Cho, used intra-vital microscopy to follow nanoparticles in real-time in mice with induced vascular inflammation. 

The nanoparticles were labeled with a fluorescent dye, and could be seen binding to and entering neutrophils clustered together on the inner walls of capillaries, but not binding to freely circulating neutrophils. If the researchers attached a drug called piceatannol, which interferes with cell-cell adhesion, to the nanoparticles, they observed that clusters of neutrophils that took up the particles detached from each other and from the blood vessel wall. 

The cells were in effect neutralized and could no longer contribute to inflammation at the site of an injury. The findings, Malik said, “show that nanoparticles can be used to deliver drugs in a highly targeted, specific fashion to activated immune cells and could be designed to treat a broad range of inflammatory diseases.” Jing Li, postdoctoral research associate in pharmacology, was also a co-author of the study. The research was supported by grants 11SDG7490013 from the American Heart Association, and grants K25HL11157, R01 HL109439 and P01 HL77806 from the National Institutes of Health

Source: http://news.uic.edu/nanoparticles-target-anti-inflammatory-drugs-where-needed#sthash.BLg29h7O.dpuf

Novel Nanotherapy Breakthrough May Help Reduce Recurrent Heart Attacks and Stroke

Icahn School of Medicine at Mount Sinai designs HDL nanoparticle to deliver statin medication inside inflamed blood vessels to prevent repeat heart attacks and stroke.

Up to 30 percent of heart attack patients suffer a new heart attack because cardiologists are unable to control inflammation inside heart arteries — the process that leads to clots rupturing and causing myocardial infarction or stroke.

But a report in Nature Communications by Icahn School of Medicine at Mount Sinai scientists showcases the development of a new technology that may provide a solution to this high risk of repeat heart attacks — and potentially help save more lives.

An international research team, led by Mount Sinai investigators, designed and tested a high-density lipoprotein (HDL) nanoparticle loaded with a statin drug. In mouse studies, they show this HDL nanotherapy is capable of directly targeting and lowering dangerous inflammation in blood vessels.

Not only could the HDL nanotherapy potentially avert repeat heart attacks, it may also have the power to reduce recurrent strokes caused by clots in brain arteries, says the study's senior investigator, Willem Mulder, PhD, Associate Professor of Radiology in the Translational and Molecular Imaging Institute at the Icahn School of Medicine at Mount Sinai.

"We envision that a safe and effective HDL nanotherapy could substantially lower cardiovascular events during the critical period of vulnerability after a heart attack or stroke," says Dr. Mulder.

"While we have much more to do to confirm clinical benefit in patients, our study shows how this nanotherapy functions biologically, and how this novel concept could potentially also work in the clinical setting to solve a critical problem," says Dr. Mulder. "This nanotherapy would be the first of its kind."

Inject HDL Statin Nanotherapy Right After Heart Attack and Stroke Treatment

The research team, led by two PhD graduate students as first authors — Raphael Duivenvoorden, MD, and Jun Tang, MS— fashioned the nanoparticle to resemble an HDL cholesterol particle. In fact, the nanoparticle binds on to the same receptors as natural HDL in order to deliver the statin drug.

Oral statin medications used by millions of people today work primarily in the liver to reduce levels of unhealthy lipids, such as low density lipoproteins (LDL), that circulate in the blood. Statins also exert a very weak dampening effect on some inflammatory cells, foremost those called macrophages that hide within plaque in the arterial walls.

It is this anti-inflammatory function that the researchers sought to bolster by designing their HDL nanotherapy.

Inflammation is the main driver of plaque buildup in arteries. Without inflammation, as well as lipid deposition in blood vessels, clots would not form. As inflammation progresses, macrophages secrete enzymes that degrade the walls of blood vessels, leading to a break in the vessel and the formation of clots. These clots can then clog arteries, leading to a heart attack or stroke.

"Levels of inflammation spike after a heart attack, which is why up to 30 percent of heart attack patients may suffer another heart attack, some while in hospital or just after discharge," says co-author Zahi Fayad, PhD, Professor of Radiology and Director of the Translational and Molecular Imaging Institute at Icahn School of Medicine at Mount Sinai. "This is the vital time to attack this inflammation culprit, which we currently are unable to do clinically right now," says Dr. Fayad. "Even with the most aggressive treatment available, repeat heart attacks do occur."

According to Mount Sinai researchers, the best way to use their HDL nanotherapy is by injection after the clot that produces a heart attack or stroke has been treated. The HDL nanoparticle would deliver the statin directly to macrophages that are driving the inflammatory response. "This could potentially and very rapidly stabilize a dangerous situation," Dr. Mulder says. "In addition, after discharge, patients would continue to use their oral statins to control LDL in their blood."

"Our study also confirms that the HDL nanoparticle is not seen as a foreign invader by the body's immune system and that it has an inherent and natural affinity to target plaque macrophages," says Jun Tang. "Our experiments demonstrated a very rapid reduction in inflammation in mice with advanced plaque buildup."

If the HDL nanotherapy works well in clinical studies, it may be possible to use it in the future as a heart attack prevention tool, according to Dr. Fayad. "If proven to be safe and effective in humans, this would be a critical advance for cardiovascular medicine. We look forward to further testing of our team's novel nanotherapy breakthrough."

Source: http://icahn.mssm.edu/about-us/news-and-events/novel-nanotherapy-breakthrough-may-help-reduce-recurrent-heart-attacks-and-stroke

Weighing particles at the attogram scale

The illustration shows a suspended nanochannel resonator (SNR),
which can directly measure the mass of individual nanoparticles
with single-attogram precision. The inset shows a depiction from
inside the embedded fluidic channel, while a DNA-origami gold
nanoparticle assembly is passing through the resonator.
IMAGE COURTESY OF SELIM OLCUM AND NATE CERMAK

New device from MIT can measure masses as small as one millionth of a trillionth of a gram, in solution.

MIT engineers have devised a way to measure the mass of particles with a resolution better than an attogram — one millionth of a trillionth of a gram. Weighing these tiny particles, including both synthetic nanoparticles and biological components of cells, could help researchers better understand their composition and function.

The system builds on a technology previously developed by Scott Manalis, an MIT professor of biological and mechanical engineering, to weigh larger particles, such as cells. This system, known as a suspended microchannel resonator (SMR), measures the particles’ mass as they flow through a narrow channel.

By shrinking the size of the entire system, the researchers were able to boost its resolution to 0.85 attograms —more than a 30-fold improvement over the previous generation of the device.

“Now we can weigh small viruses, extracellular vesicles, and most of the engineered nanoparticles that are being used for nanomedicine,” says Selim Olcum, a postdoc in Manalis’ lab and one of the lead authors of a paper describing the system in this week’s issue of the Proceedings of the National Academy of Sciences.

Graduate student Nathan Cermak is also a lead author of the paper, and Manalis, a member of MIT’s Koch Institute for Integrative Cancer Research, is the paper’s senior author. Researchers from the labs of MIT professors and Koch Institute members Angela Belcher and Sangeeta Bhatia also contributed to the study.

A small sensor for small particles

Manalis first developed the SMR system in 2007 to measure the mass of living cells, as well as particles as small as a femtogram (one quadrillionth of a gram, or 1,000 attograms). Since then, his lab has used the device to track cell growth over time,measure cell density, and measure other physical properties, such as stiffness. 

The original mass sensor consists of a fluid-filled microchannel etched in a tiny silicon cantilever that vibrates inside a vacuum cavity. As cells or particles flow through the channel, one at a time, their mass slightly alters the cantilever’s vibration frequency. The mass of the particle can be calculated from that change in frequency.

To make the device sensitive to smaller masses, the researchers had to shrink the size of the cantilever, which behaves much like a diving board, Olcum says. When a diver bounces at the end of a diving board, it vibrates with a very large amplitude and low frequency. When the diver plunges into the water, the board begins to vibrate much faster because the total mass of the board has dropped considerably.

To measure smaller masses, a smaller “diving board” is required. “If you’re measuring nanoparticles with a large cantilever, it’s like having a huge diving board with a tiny fly on it. When the fly jumps off, you don’t notice any difference. That’s why we had to make very tiny diving boards,” Olcum says.

In a previous study, researchers in Manalis’ lab built a 50-micron cantilever — about one-tenth the size of the cantilever used for measuring cells. That system, known as a suspended nanochannel resonator (SNR), was able to weigh particles as light as 77 attograms at a rate of a particle or two per second.

The cantilever in the new version of the SNR device is 22.5 microns long, and the channel that runs across it is 1 micron wide and 400 nanometers deep. This miniaturization makes the system more sensitive because it increases the cantilever’s vibration frequency. At higher frequencies, the cantilever is more responsive to smaller changes in mass.

The researchers got another boost in resolution by switching the source for the cantilever’s vibration from an electrostatic to a piezoelectric excitation, which produces a larger amplitude and, in turn, decreases the impact of spurious vibrations that interfere with the signal they are trying to measure.

With this system, the researchers can measure nearly 30,000 particles in a little more than 90 minutes. “In the span of a second, we’ve got four or five particles going through, and we could potentially increase the concentration and have particles going through faster,” Cermak says. 

Particle analysis

To demonstrate the device’s usefulness in analyzing engineered nanoparticles, the MIT team weighed nanoparticles made of DNA bound to tiny gold spheres, which allowed them to determine how many gold spheres were bound to each DNA-origami scaffold. That information can be used to assess yield, which is important for developing precise nanostructures, such as scaffolds for nanodevices. 

The researchers also tested the SNR system on biological nanoparticles called exosomes — vesicles that carry proteins, RNA, or other molecules secreted by cells — which are believed to play a role in signaling between distant locations in the body.

They found that exosomes secreted by liver cells and fibroblasts (cells that make up connective tissue) had different profiles of mass distribution, suggesting that it may be possible to distinguish vesicles that originate from different cells and may have different biological functions. 

The researchers are now investigating using the SNR device to detect exosomes in the blood of patients with glioblastoma (GBM), a type of brain cancer. This type of tumor secretes large quantities of exosomes, and tracking changes in their concentration could help doctors monitor patients as they are treated.

Glioblastoma exosomes can now be detected by mixing blood samples with magnetic nanoparticles coated with antibodies that bind to markers found on vesicle surfaces, but the SNR could provide a simpler test. 

“We’re particularly excited about using the high precision of the SNR to quantify microvesicles in the blood of GBM patients. Although affinity-based approaches do exist for isolating subsets of microvesicles, the SNR could potentially provide a label-free means of enumerating microvesicles that is independent of their surface expression,” Manalis says. 

The research was funded by the U.S. Army Research Office through the Institute for Collaborative Biotechnologies, the Center for Integration of Medicine and Innovative Technology, the National Science Foundation, and the National Cancer Institute.

Source: http://web.mit.edu/newsoffice/2014/weighing-particles-at-the-attogram-scale-0113.html