Tag Archives: nanoparticles

Investigating nanoparticles and their environmental impact for industry?

It seems the Center for the Environmental Implications of Nanotechnology (CEINT) at Duke University (North Carolina, US) is making an adjustment to its focus and opening the door to industry, as well as, government research. It has for some years (my first post about the CEINT at Duke University is an Aug. 15, 2011 post about its mesocosms) been focused on examining the impact of nanoparticles (also called nanomaterials) on plant life and aquatic systems. This Jan. 9, 2017 US National Science Foundation (NSF) news release (h/t Jan. 9, 2017 Nanotechnology Now news item) provides a general description of the work,

We can’t see them, but nanomaterials, both natural and manmade, are literally everywhere, from our personal care products to our building materials–we’re even eating and drinking them.

At the NSF-funded Center for Environmental Implications of Nanotechnology (CEINT), headquartered at Duke University, scientists and engineers are researching how some of these nanoscale materials affect living things. One of CEINT’s main goals is to develop tools that can help assess possible risks to human health and the environment. A key aspect of this research happens in mesocosms, which are outdoor experiments that simulate the natural environment – in this case, wetlands. These simulated wetlands in Duke Forest serve as a testbed for exploring how nanomaterials move through an ecosystem and impact living things.

CEINT is a collaborative effort bringing together researchers from Duke, Carnegie Mellon University, Howard University, Virginia Tech, University of Kentucky, Stanford University, and Baylor University. CEINT academic collaborations include on-going activities coordinated with faculty at Clemson, North Carolina State and North Carolina Central universities, with researchers at the National Institute of Standards and Technology and the Environmental Protection Agency labs, and with key international partners.

The research in this episode was supported by NSF award #1266252, Center for the Environmental Implications of NanoTechnology.

The mention of industry is in this video by O’Brien and Kellan, which describes CEINT’s latest work ,

Somewhat similar in approach although without a direction reference to industry, Canada’s Experimental Lakes Area (ELA) is being used as a test site for silver nanoparticles. Here’s more from the Distilling Science at the Experimental Lakes Area: Nanosilver project page,

Water researchers are interested in nanotechnology, and one of its most commonplace applications: nanosilver. Today these tiny particles with anti-microbial properties are being used in a wide range of consumer products. The problem with nanoparticles is that we don’t fully understand what happens when they are released into the environment.

The research at the IISD-ELA [International Institute for Sustainable Development Experimental Lakes Area] will look at the impacts of nanosilver on ecosystems. What happens when it gets into the food chain? And how does it affect plants and animals?

Here’s a video describing the Nanosilver project at the ELA,

You may have noticed a certain tone to the video and it is due to some political shenanigans, which are described in this Aug. 8, 2016 article by Bartley Kives for the Canadian Broadcasting Corporation’s (CBC) online news.

Nanoparticle ‘caterpillars’ and immune system ‘crows’

This University of Colorado work fits in nicely with other efforts to ensure that nanoparticle medical delivery systems get to their destinations. From a Dec. 19, 2016 news item on phys.org,

In the lab, doctors can attach chemotherapy to nanoparticles that target tumors, and can use nanoparticles to enhance imaging with MRI, PET and CT scans. Unfortunately, nanoparticles look a lot like pathogens – introducing nanoparticles to the human body can lead to immune system activation in which, at best, nanoparticles are cleared before accomplishing their purpose, and at worst, the onset of dangerous allergic reaction. A University of Colorado Cancer Center paper published today [Dec. 19, 2016] in the journal Nature Nanotechnology details how the immune system recognizes nanoparticles, potentially paving the way to counteract or avoid this detection.

Specifically, the study worked with dextran-coated iron oxide nanoparticles, a promising and versatile class of particles used as drug-delivery vehicles and MRI contrast enhancers in many studies. As their name implies, the particles are tiny flecks of iron oxide encrusted with sugar chains.

“We used several sophisticated microscopy approaches to understand that the particles basically look like caterpillars,” says Dmitri Simberg, PhD, investigator at the CU Cancer Center and assistant professor in the Skaggs School of Pharmacy and Pharmaceutical Sciences, the paper’s senior author.

The comparison is striking: the iron oxide particle is the caterpillar’s body, which is surrounded by fine hairs of dextran.

Caption: University of Colorado Cancer Study shows how nanoparticles activate the complement system, potentially paving the way for expanded use of these technologies.
Credit: University of Colorado Cancer Center

A Dec. 19, 2016 University of Colorado news release on EurekAlert, which originated the news item, describes the work in more detail,

If Simberg’s dextran-coated iron oxide nanoparticles are caterpillars, then the immune system is a fat crow that would eat them – that is, if it can find them. In fact, the immune system has evolved for exactly this purpose – to find and “eat” foreign particles – and rather than one homogenous entity is actually composed of a handful of interrelated systems, each specialized to counteract a specific form of invading particle.

Simberg’s previous work shows that it is the immune subcomponent called the complement system that most challenges nanoparticles. Basically, the complement system is a group of just over 30 proteins that circulate through the blood and attach to invading particles and pathogens. In humans, complement system activation requires that three proteins come together on a particle -C3b, Bb and properdin – which form a stable complex called C3-convertase.

“The whole complement system activation starts with the assembly of C3-convertase,” Simberg says. “In this paper, we ask the question of how the complement proteins actually recognize the nanoparticle surface. How is this whole reaction triggered?”

First, it was clear that the dextran coating that was supposed to protect the nanoparticles from human complement attack was not doing its job. Simberg and colleagues could see complement proteins literally invade the barrier of dextran hairs.

“Electron microscopy images show protein getting inside the particle to touch the iron oxide core,” Simberg says.

In fact, as long as the nanoparticle coating allowed the nanoparticle to absorb proteins from blood, the C3 convertase was assembled and activated on these proteins. The composition of the coating was irrelevant – if any blood protein was able to bind to nanoparticles, it always led to complement activation. Moreover, Simberg and colleagues also showed that complement system activation is a dynamic and ongoing process – blood proteins and C3 convertase constantly dissociate from nanoparticles, and new proteins and C3 convertases bind to the particles, continuing the cascade of immune system activation. The group also demonstrated that this dynamic assembly of complement proteins occurs not only in the test tubes but also in living organisms as particles circulate in blood.

Simberg suggests that the work points to challenges and three possible strategies to avoid complement system activation by nanoparticles: “First, we could try to change the nanoparticle coating so that it can’t absorb proteins, which is a difficult task; second, we could better understand the composition of proteins absorbed from blood on the particle surface that allow it to bind complement proteins; and third, there are natural inhibitors of complement activation – for example blood Factor H – but in the context of nanoparticles, it’s not strong enough to stop complement activation. Perhaps we could get nanoparticles to attract more Factor H to decrease this activation.”

At one point, the concept of nanomedicine seemed as if it would be simple – engineers and chemists would make a nanoparticle with affinity for tumor tissue and then attach a drug molecule to it. Or they would inject nanoparticles into patients that would improve the resolution of diagnostic imaging. When the realities associated with the use of nanoparticles in the landscape of the human immune system proved more challenging, many researchers realized the need to step back from possible clinical use to better understand the mechanisms that challenge nanoparticle use.

“This basic groundwork is absolutely necessary,” says Seyed Moein Moghimi, PhD, nanotechnologist at Durham University, UK, and the coauthor of the Simberg paper. “It’s essential that we learn to control the process of immune recognition so that we can bridge between the promise that nanoparticles demonstrate in the lab and their use with real patients in the real world.”

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

Complement proteins bind to nanoparticle protein corona and undergo dynamic exchange in vivo by Fangfang Chen, Guankui Wang, James I. Griffin, Barbara Brenneman, Nirmal K. Banda, V. Michael Holers, Donald S. Backos, LinPing Wu, Seyed Moein Moghimi, & Dmitri Simberg. Nature Nanotechnology  (2016) doi:10.1038/nnano.2016.269 19 December 2016

This paper is behind a paywall.

I have a few previous postings about nanoparticles as drug delivery systems which have yet to fulfill their promise. There’s the April 27, 2016 posting (How many nanoparticle-based drugs does it take to kill a cancer tumour? More than 1%) and the Sept. 9, 2016 posting (Discovering how the liver prevents nanoparticles from reaching cancer cells).

The character of water: both types

This is to use an old term, ‘mindblowing’. Apparently, there are two types of the liquid we call water according to a Nov. 10, 2016 news item on phys.org,

There are two types of liquid water, according to research carried out by an international scientific collaboration. This new peculiarity adds to the growing list of strange phenomena in what we imagine is a simple substance. The discovery could have implications for making and using nanoparticles as well as in understanding how proteins fold into their working shape in the body or misfold to cause diseases such as Alzheimer’s or CJD [Creutzfeldt-Jakob Disease].

A Nov. 10, 2016 Inderscience Publishers news release, which originated the news item, expands on the theme,

Writing in the International Journal of Nanotechnology, Oxford University’s Laura Maestro and her colleagues in Italy, Mexico, Spain and the USA, explain how the physical and chemical properties of water have been studied for more than a century and revealed some odd behavior not seen in other substances. For instance, when water freezes it expands. By contrast, almost every other known substance contracts when it is cooled. Water also exists as solid, liquid and gas within a very small temperature range (100 degrees Celsius) whereas the melting and boiling points of most other compounds span a much greater range.

Many of water’s bizarre properties are due to the molecule’s ability to form short-lived connections with each other known as hydrogen bonds. There is a residual positive charge on the hydrogen atoms in the V-shaped water molecule either or both of which can form such bonds with the negative electrons on the oxygen atom at the point of the V. This makes fleeting networks in water possible that are frozen in place when the liquid solidifies. They bonds are so short-lived that they do not endow the liquid with any structure or memory, of course.

The team has looked closely at several physical properties of water like its dielectric constant (how well an electric field can permeate a substance) or the proton-spin lattice relaxation (the process by which the magnetic moments of the hydrogen atoms in water can lose energy having been excited to a higher level). They have found that these phenomena seem to flip between two particular characters at around 50 degrees Celsius, give or take 10 degrees, i.e. from 40 to 60 degrees Celsius. The effect is that thermal expansion, speed of sound and other phenomena switch between two different states at this crossover temperature.

These two states could have important implications for studying and using nanoparticles where the character of water at the molecule level becomes important for the thermal and optical properties of such particles. Gold and silver nanoparticles are used in nanomedicine for diagnostics and as antibacterial agents, for instance. Moreover, the preliminary findings suggest that the structure of liquid water can strongly influence the stability of proteins and how they are denatured at the crossover temperature, which may well have implications for understanding protein processing in the food industry but also in understanding how disease arises when proteins misfold.

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

On the existence of two states in liquid water: impact on biological and nanoscopic systems
by L.M. Maestro, M.I. Marqués, E. Camarillo, D. Jaque, J. García Solé, J.A. Gonzalo, F. Jaque, Juan C. Del Valle, F. Mallamace, H.E. Stanley.
International Journal of Nanotechnology (IJNT), Vol. 13, No. 8/9, 2016 DOI: 10.1504/IJNT.2016.079670

This paper is behind a paywall.

Mimicking rain and sun to test plastic for nanoparticle release

One of Canada’s nanotechnology experts once informed a House of Commons Committee on Health that nanoparticles encased in plastic (he was talking about cell phones) weren’t likely to harm you except in two circumstances (when workers were using them in the manufacturing process and when the product was being disposed of). Apparently, under some circumstances, that isn’t true any more. From a Sept. 30, 2016 news item on Nanowerk,

If the 1967 film “The Graduate” were remade today, Mr. McGuire’s famous advice to young Benjamin Braddock would probably be updated to “Plastics … with nanoparticles.” These days, the mechanical, electrical and durability properties of polymers—the class of materials that includes plastics—are often enhanced by adding miniature particles (smaller than 100 nanometers or billionths of a meter) made of elements such as silicon or silver. But could those nanoparticles be released into the environment after the polymers are exposed to years of sun and water—and if so, what might be the health and ecological consequences?

A Sept. 30, 2016 US National Institute of Standards and Technology (NIST) news release, which originated the news item, describes how the research was conducted and its results (Note: Links have been removed),

In a recently published paper (link is external), researchers from the National Institute of Standards and Technology (NIST) describe how they subjected a commercial nanoparticle-infused coating to NIST-developed methods for accelerating the effects of weathering from ultraviolet (UV) radiation and simulated washings of rainwater. Their results indicate that humidity and exposure time are contributing factors for nanoparticle release, findings that may be useful in designing future studies to determine potential impacts.

In their recent experiment, the researchers exposed multiple samples of a commercially available polyurethane coating containing silicon dioxide nanoparticles to intense UV radiation for 100 days inside the NIST SPHERE (Simulated Photodegradation via High-Energy Radiant Exposure), a hollow, 2-meter (7-foot) diameter black aluminum chamber lined with highly UV reflective material that bears a casual resemblance to the Death Star in the film “Star Wars.” For this study, one day in the SPHERE was equivalent to 10 to 15 days outdoors. All samples were weathered at a constant temperature of 50 degrees Celsius (122 degrees Fahrenheit) with one group done in extremely dry conditions (approximately 0 percent humidity) and the other in humid conditions (75 percent humidity).

To determine if any nanoparticles were released from the polymer coating during UV exposure, the researchers used a technique they created and dubbed “NIST simulated rain.” Filtered water was converted into tiny droplets, sprayed under pressure onto the individual samples, and then the runoff—with any loose nanoparticles—was collected in a bottle. This procedure was conducted at the beginning of the UV exposure, at every two weeks during the weathering run and at the end. All of the runoff fluids were then analyzed by NIST chemists for the presence of silicon and in what amounts. Additionally, the weathered coatings were examined with atomic force microscopy (AFM) and scanning electron microscopy (SEM) to reveal surface changes resulting from UV exposure.

Both sets of coating samples—those weathered in very low humidity and the others in very humid conditions—degraded but released only small amounts of nanoparticles. The researchers found that more silicon was recovered from the samples weathered in humid conditions and that nanoparticle release increased as the UV exposure time increased. Microscopic examination showed that deformations in the coating surface became more numerous with longer exposure time, and that nanoparticles left behind after the coating degraded often bound together in clusters.

“These data, and the data from future experiments of this type, are valuable for developing computer models to predict the long-term release of nanoparticles from commercial coatings used outdoors, and in turn, help manufacturers, regulatory officials and others assess any health and environmental impacts from them,” said NIST research chemist Deborah Jacobs, lead author on the study published in the Journal of Coatings Technology and Research (link is external).

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

Surface degradation and nanoparticle release of a commercial nanosilica/polyurethane coating under UV exposure by Deborah S. Jacobs, Sin-Ru Huang, Yu-Lun Cheng, Savelas A. Rabb, Justin M. Gorham, Peter J. Krommenhoek, Lee L. Yu, Tinh Nguyen, Lipiin Sung. J Coat Technol Res (2016) 13: 735. doi:10.1007/s11998-016-9796-2 First published online 13 July 2016

This paper is behind a paywall.

For anyone interested in the details about the House of Commons nano story I told at the start of this post, here’s the June 23, 2010 posting where I summarized the hearing on nanotechnology. If you scroll down about 50% of the way, you’ll find Dr. Nils Petersen’s (then director of Canada’s National Institute of Nanotechnology) comments about nanoparticles being encased. The topic had been nanosunscreens and he was describing the conditions under which he believed nanoparticles could be dangerous.

Tattoo therapy for chronic disease?

It’s good to wake up to something truly new. In this case, it’s using tattoos and nanoparticles for medical applications. From a Sept. 22, 2016 news item on ScienceDaily,

A temporary tattoo to help control a chronic disease might someday be possible, according to scientists at Baylor College of Medicine [Texas, US] who tested antioxidant nanoparticles created at Rice University [Texas, US].

A Sept. 22, 2016 Rice University news release, which originated the news item, provides more information and some good explanations of the terms used (Note: Links have been removed),

A proof-of-principle study led by Baylor scientist Christine Beeton published today by Nature’s online, open-access journal Scientific Reports shows that nanoparticles modified with polyethylene glycol are conveniently choosy as they are taken up by cells in the immune system.

That could be a plus for patients with autoimmune diseases like multiple sclerosis, one focus of study at the Beeton lab. “Placed just under the skin, the carbon-based particles form a dark spot that fades over about one week as they are slowly released into the circulation,” Beeton said.

T and B lymphocyte cells and macrophages are key components of the immune system. However, in many autoimmune diseases such as multiple sclerosis, T cells are the key players. One suspected cause is that T cells lose their ability to distinguish between invaders and healthy tissue and attack both.

In tests at Baylor, nanoparticles were internalized by T cells, which inhibited their function, but ignored by macrophages. “The ability to selectively inhibit one type of cell over others in the same environment may help doctors gain more control over autoimmune diseases,” Beeton said.

“The majority of current treatments are general, broad-spectrum immunosuppressants,” said Redwan Huq, lead author of the study and a graduate student in the Beeton lab. “They’re going to affect all of these cells, but patients are exposed to side effects (ranging) from infections to increased chances of developing cancer. So we get excited when we see something new that could potentially enable selectivity.” Since the macrophages and other splenic immune cells are unaffected, most of a patient’s existing immune system remains intact, he said.

The soluble nanoparticles synthesized by the Rice lab of chemist James Tour have shown no signs of acute toxicity in prior rodent studies, Huq said. They combine polyethylene glycol with hydrophilic carbon clusters, hence their name, PEG-HCCs. The carbon clusters are 35 nanometers long, 3 nanometers wide and an atom thick, and bulk up to about 100 nanometers in globular form with the addition of PEG. They have proven to be efficient scavengers of reactive oxygen species called superoxide molecules, which are expressed by cells the immune system uses to kill invading microorganisms.

T cells use superoxide in a signaling step to become activated. PEG-HCCs remove this superoxide from the T cells, preventing their activation without killing the cells.

Beeton became aware of PEG-HCCs during a presentation by former Baylor graduate student Taeko Inoue, a co-author of the new study. “As she talked, I was thinking, ‘That has to work in models of multiple sclerosis,’” Beeton said. “I didn’t have a good scientific rationale, but I asked for a small sample of PEG-HCCs to see if they affected immune cells.

“We found they affected the T lymphocytes and not the other splenic immune cells, like the macrophages. It was completely unexpected,” she said.

The Baylor lab’s tests on animal models showed that small amounts of PEG-HCCs injected under the skin are slowly taken up by T lymphocytes, where they collect and inhibit the cell’s function. They also found the nanoparticles did not remain in T cells and dispersed within days after uptake by the cells.

“That’s an issue because you want a drug that’s in the system long enough to be effective, but not so long that, if you have a problem, you can’t remove it,” Beeton said. “PEG-HCCs can be administered for slow release and don’t stay in the system for long. This gives us much better control over the circulating half-life.”

“The more we study the abilities of these nanoparticles, the more surprised we are at how useful they could be for medical applications,” Tour said. The Rice lab has published papers with collaborators at Baylor and elsewhere on using functionalized nanoparticles to deliver cancer drugs to tumors and to quench the overproduction of superoxides after traumatic brain injuries.

Beeton suggested delivering carbon nanoparticles just under the skin rather than into the bloodstream would keep them in the system longer, making them more available for uptake by T cells. And the one drawback – a temporary but visible spot on the skin that looks like a tattoo – could actually be a perk to some.

“We saw it made a black mark when we injected it, and at first we thought that’s going to be a real problem if we ever take it into the clinic,” Beeton said. “But we can work around that. We can inject into an area that’s hidden, or use micropattern needles and shape it.

“I can see doing this for a child who wants a tattoo and could never get her parents to go along,” she said. “This will be a good way to convince them.”

The research was supported by Baylor College of Medicine, the National Multiple Sclerosis Society, National Institutes of Health, the Dan L. Duncan Cancer Center, John S. Dunn Gulf Coast Consortium for Chemical Genomics and the U.S. Army-funded Traumatic Brain Injury Consortium.

That’s an interesting list of funders at the end of the news release.

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

Preferential uptake of antioxidant carbon nanoparticles by T lymphocytes for immunomodulation by Redwan Huq, Errol L. G. Samuel, William K. A. Sikkema, Lizanne G. Nilewski, Thomas Lee, Mark R. Tanner, Fatima S. Khan, Paul C. Porter, Rajeev B. Tajhya, Rutvik S. Patel, Taeko Inoue, Robia G. Pautler, David B. Corry, James M. Tour, & Christine Beeton. Scientific Reports 6, Article number: 33808 (2016) doi:10.1038/srep33808 Published online: 22 September 2016

This paper is open access.

Here’s an image provided by the researchers,

Polyethylene glycol-hydrophilic carbon clusters developed at Rice University were shown to be selectively taken up by T cells, which inhibits their function, in tests at Baylor College of Medicine. The researchers said the nanoparticles could lead to new strategies for controlling autoimmune diseases like multiple sclerosis. (Credit: Errol Samuel/Rice University) - See more at: http://news.rice.edu/2016/09/22/tattoo-therapy-could-ease-chronic-disease/#sthash.sIfs3b0S.dpuf

Polyethylene glycol-hydrophilic carbon clusters developed at Rice University were shown to be selectively taken up by T cells, which inhibits their function, in tests at Baylor College of Medicine. The researchers said the nanoparticles could lead to new strategies for controlling autoimmune diseases like multiple sclerosis. (Credit: Errol Samuel/Rice University)

Counteracting chemotherapy resistance with nanoparticles that mimic salmonella

Given the reputation that salmonella (for those who don’t know, it’s a toxin you don’t want to find in your food) has, a nanoparticle which mimics its effects has a certain cachet. An Aug. 22, 2016 news item on Nanowerk,

Researchers at the University of Massachusetts Medical School have designed a nanoparticle that mimics the bacterium Salmonella and may help to counteract a major mechanism of chemotherapy resistance.

Working with mouse models of colon and breast cancer, Beth McCormick, Ph.D., and her colleagues demonstrated that when combined with chemotherapy, the nanoparticle reduced tumor growth substantially more than chemotherapy alone.

Credit: Rocky Mountain Laboratories,NIAID,NIHColor-enhanced scanning electron micrograph showing Salmonella typhimurium (red) invading cultured human cells.

Credit: Rocky Mountain Laboratories,NIAID,NIHColor-enhanced scanning electron micrograph showing Salmonella typhimurium (red) invading cultured human cells.

An Aug. 22, 2016 US National Institute of Cancer news release, which originated the news item, explains the research in more detail,

A membrane protein called P-glycoprotein (P-gp) acts like a garbage chute that pumps waste, foreign particles, and toxins out of cells. P-gp is a member of a large family of transporters, called ATP-binding cassette (ABC) transporters, that are active in normal cells but also have roles in cancer and other diseases. For instance, cancer cells can co-opt P-gp to rid themselves of chemotherapeutic agents, severely limiting the efficacy of these drugs.

In previous work, Dr. McCormick and her colleagues serendipitously discovered that Salmonella enterica, a bacterium that causes food poisoning, decreases the amount of P-gp on the surface of intestinal cells. Because Salmonella has the capacity to grow selectively in cancer cells, the researchers wondered whether there was a way to use the bacterium to counteract chemotherapy resistance caused by P-gp.

“While trying to understand how Salmonella invades the human host, we made this other observation that may be relevant to cancer therapeutics and multidrug resistance,” explained Dr. McCormick.

Salmonella and Cancer Cells

To determine the specific bacterial component responsible for reducing P-gp levels, the researchers engineered multiple Salmonella mutant strains and tested their effect on P-gp levels in colon cells. They found that a Salmonella strain lacking the bacterial protein SipA was unable to reduce P-gp levels in the colon of mice or in a human colon cancer cell line. Salmonella secretes SipA, along with other proteins, to help the bacterium invade human cells.

The researchers then showed that treatment with SipA protein alone decreased P-gp levels in cell lines of human colon cancer, breast cancer, bladder cancer, and lymphoma.

Because P-gp can pump drugs out of cells, the researchers next sought to determine whether SipA treatment would prevent cancer cells from expelling chemotherapy drugs.

When they treated human colon cancer cells with the chemotherapy agents doxorubicin or vinblastine, with or without SipA, they found that the addition of SipA increased drug retention inside the cells. SipA also increased the cancer cells’ sensitivity to both drugs, suggesting that it could possibly be used to enhance chemotherapy.

“Through millions of years of co-evolution, Salmonella has figured out a way to remove this transporter from the surface of intestinal cells to facilitate host infection,” said Dr. McCormick. “We capitalized on the organism’s ability to perform that function.”

A Nanoparticle Mimic

It would not be feasible to infect people with the bacterium, and SipA on its own will likely deteriorate quickly in the bloodstream, coauthor Gang Han, Ph.D., of the University of Massachusetts Medical School, explained in a press release. The researchers therefore fused SipA to gold nanoparticles, generating what they refer to as a nanoparticle mimic of Salmonella. They designed the nanoparticle to enhance the stability of SipA, while retaining its ability to interact with other proteins.

In an effort to target tumors without harming healthy tissues, the researchers used a nanoparticle of specific size that should only be able to access the tumor tissue due to its “leaky” architecture. “Because of this property, we are hoping to be able to avoid negative effects to healthy tissues,” said Dr. McCormick. Another benefit of this technology is that the nanoparticle can be modified to enhance tumor targeting and minimize the potential for side effects, she added.

The researchers showed that this nanoparticle was 100 times more effective than SipA protein alone at reducing P-gp levels in a human colon cancer cell line. The enhanced function of the nanoparticle is likely due to stabilization of SipA, explained the researchers.

The team then tested the nanoparticle in a mouse model of colon cancer, because this cancer type is known to express high levels of P-gp. When they treated tumor-bearing mice with the nanoparticle plus doxorubicin, P-gp levels dropped and the tumors grew substantially less than in mice treated with the nanoparticle or doxorubicin alone. The researchers observed similar results in a mouse model of human breast cancer.

There are concerns about the potential effect of nanoparticles on normal tissues. “P-gp has evolved as a defense mechanism” to rid healthy cells of toxic molecules, said Suresh Ambudkar, Ph.D., deputy chief of the Laboratory of Cell Biology in NCI’s Center for Cancer Research. It plays an important role in protecting cells of the blood-brain barrier, liver, testes, and kidney. “So when you try to interfere with that, you may create problems,” he said.

The researchers, however, found no evidence of nanoparticle accumulation in the brain, heart, kidney, or lungs of mice, nor did it appear to cause toxicity. They did observe that the nanoparticles accumulated in the liver and spleen, though this was expected because these organs filter the blood, said Dr. McCormick.

Moving Forward

The research team is moving forward with preclinical studies of the SipA nanoparticle to test its safety and toxicity, and to establish appropriate dosage levels.

However, Dr. Ambudkar noted, “the development of drug resistance in cancer cells is a multifactorial process. In addition to the ABC transporters, other phenomena are involved, such as drug metabolism.” And because there is a large family of ABC transporters, one transporter can compensate if another is blocked, he explained.

For the last 25 years, clinical trials with drugs that inhibit P-gp have failed to overcome chemotherapy resistance, Dr. Ambudkar said. Tackling the issue of multidrug resistance in cancer, he continued, “is not something that can be solved easily.”

Dr. McCormick and her team are also pursuing research to better characterize and understand the biology of SipA. “We are not naïve about the complexity of the problem,” she said. “However, if we know more about the biology, we believe we can ultimately make a better drug.”

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

A Salmonella nanoparticle mimic overcomes multidrug resistance in tumours by Regino Mercado-Lubo, Yuanwei Zhang, Liang Zhao, Kyle Rossi, Xiang Wu, Yekui Zou, Antonio Castillo, Jack Leonard, Rita Bortell, Dale L. Greiner, Leonard D. Shultz, Gang Han, & Beth A. McCormick. Nature Communications 7, Article number: 12225  doi:10.1038/ncomms12225 Published 25 July 2016

This paper is open access.

Nanoparticles could make blood clot faster

It was the 252nd meeting for the American Chemical Society from Aug. 21 – 25, 2016 and that meant a flurry of news about the latest research. From an Aug. 23, 2016 news item on Nanowerk,

Whether severe trauma occurs on the battlefield or the highway, saving lives often comes down to stopping the bleeding as quickly as possible. Many methods for controlling external bleeding exist, but at this point, only surgery can halt blood loss inside the body from injury to internal organs. Now, researchers have developed nanoparticles that congregate wherever injury occurs in the body to help it form blood clots, and they’ve validated these particles in test tubes and in vivo [animal testing].

The researchers will present their work today [Aug. 22, 2016] at the 252nd National Meeting & Exposition of the American Chemical Society (ACS). ACS, the world’s largest scientific society, is holding the meeting here through Thursday. It features more than 9,000 presentations on a wide range of science topics.

An Aug. 22, 2016 American Chemical Society (ACS) news release (also on EurekAlert), which originated the news item, provided more detail,

“When you have uncontrolled internal bleeding, that’s when these particles could really make a difference,” says Erin B. Lavik, Sc.D. “Compared to injuries that aren’t treated with the nanoparticles, we can cut bleeding time in half and reduce total blood loss.”

Trauma remains a top killer of children and younger adults, and doctors have few options for treating internal bleeding. To address this great need, Lavik’s team developed a nanoparticle that acts as a bridge, binding to activated platelets and helping them join together to form clots. To do this, the nanoparticle is decorated with a molecule that sticks to a glycoprotein found only on the activated platelets.

Initial studies suggested that the nanoparticles, delivered intravenously, helped keep rodents from bleeding out due to brain and spinal injury, Lavik says. But, she acknowledges, there was still one key question: “If you are a rodent, we can save your life, but will it be safe for humans?”

As a step toward assessing whether their approach would be safe in humans, they tested the immune response toward the particles in pig’s blood. If a treatment triggers an immune response, it would indicate that the body is mounting a defense against the nanoparticle and that side effects are likely. The team added their nanoparticles to pig’s blood and watched for an uptick in complement, a key indicator of immune activation. The particles triggered complement in this experiment, so the researchers set out to engineer around the problem.

“We made a battery of particles with different charges and tested to see which ones didn’t have this immune-response effect,” Lavik explains. “The best ones had a neutral charge.” But neutral nanoparticles had their own problems. Without repulsive charge-charge interactions, the nanoparticles have a propensity to aggregate even before being injected. To fix this issue, the researchers tweaked their nanoparticle storage solution, adding a slippery polymer to keep the nanoparticles from sticking to each other.

Lavik also developed nanoparticles that are stable at higher temperatures, up to 50 degrees Celsius (122 degrees Fahrenheit). This would allow the particles to be stored in a hot ambulance or on a sweltering battlefield.

In future studies, the researchers will test whether the new particles activate complement in human blood. Lavik also plans to identify additional critical safety studies they can perform to move the research forward. For example, the team needs to be sure that the nanoparticles do not cause non-specific clotting, which could lead to a stroke. Lavik is hopeful though that they could develop a useful clinical product in the next five to 10 years.

It’s not unusual for scientists to give an estimate of 5 – 10 years before their science reaches the market.  Another popular range is 3 – 5 years.

Discovering how the liver prevents nanoparticles from reaching cancer cells

There’s a lot of excitement about nanoparticles as enabling a precise drug delivery system but to date results have been disappointing as a team of researchers at the University of Toronto (Canada) noted recently (see my April 27, 2016 posting). According to those researchers, one of the main problems with the proposed nanoparticle drug delivery system is that we don’t understand how the body delivers materials to cells and disappointingly few nanoparticles (less than 1%) make their way to tumours. That situation may be changing.

An Aug. 19, 2016 news item on Nanowerk announces the latest research from the University of Toronto,

The emerging field of nanomedicine holds great promise in the battle against cancer. Particles the size of protein molecules can be customized to carry tumour-targeting drugs and destroy cancer cells without harming healthy tissue.

But here’s the problem: when nanoparticles are administered into the body, more than 99 per cent of them become trapped in non-targeted organs, such as the liver and spleen. These nanoparticles are not delivered to the site of action to carry out their intended function.

To solve this problem, researchers at the University of Toronto and the University Health Network have figured out how the liver and spleen trap intact nanoparticles as they move through the organ. “If you want to unlock the promise of nanoparticles, you have to understand and solve the problem of the liver,” says Dr. Ian McGilvray, a transplant surgeon at the Toronto General Hospital and scientist at the Toronto General Research Institute (TGRI).

An Aug. 15, 2016 University of Toronto news release by Luke Ng, which originated the news item, expands on the theme,

In a recent paper in the journal Nature Materials, the researchers say that as nanoparticles move through the liver sinusoid, the flow rate slows down 1,000 times, which increases the interaction of the nanoparticles all of types of liver cells. This was a surprising finding because the current thought is that Kupffer cells, responsible for toxin breakdown in the liver, are the ones that gobbles [sic] up the particles.  This study found that liver B-cells and liver sinusoidal endothelial cells are also involved and that the cell phenotype also matters.

“We know that the liver is the principle organ controlling what gets absorbed by our bodies and what gets filtered out—it governs our everyday biological functions,” says Dr. Kim Tsoi (… [and] research partner Sonya MacParland), a U of T orthopaedic surgery resident, and a first author of the paper, who completed her PhD in biomedical engineering with Warren Chan (IBBME). “But nanoparticle drug delivery is a newer approach and we haven’t had a clear picture of how they interact with the liver—until now.”

Tsoi and MacParland first examined both the speed and location of their engineered nanoparticles as they moved through the liver.

“This gives us a target to focus on,” says MacParland, an immunology post-doctoral fellow at U of T and TGRI. “Knowing the specific cells to modify will allow us to eventually deliver more of the nanoparticles to their intended target, attacking only the pathogens or tumours, while bypassing healthy cells.”

“Many prior studies that have tried to reduce nanomaterial clearance in the liver have focused on the particle design itself,” says Chan. “But our work now gives greater insight into the biological mechanisms underpinning our experimental observations — now we hope to use our fundamental findings to help design nanoparticles that work with the body, rather than against it.”

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

Mechanism of hard-nanomaterial clearance by the liver by Kim M. Tsoi, Sonya A. MacParland, Xue-Zhong Ma, Vinzent N. Spetzler, Juan Echeverri, Ben Ouyang, Saleh M. Fadel, Edward A. Sykes, Nicolas Goldaracena, Johann M. Kaths, John B. Conneely, Benjamin A. Alman, Markus Selzner, Mario A. Ostrowski, Oyedele A. Adeyi, Anton Zilman, Ian D. McGilvray, & Warren C. W. Chan. Nature Materials (2016) doi:10.1038/nmat4718 Published online 15 August 2016

This paper is behind a paywall.

Open access to nanoparticles and nanocomposites

One of the major issues for developing nanotechnology-enabled products is access to nanoparticles and nanocomposites. For example, I’ve had a number of requests from entrepreneurs for suggestions as to how to access cellulose nanocrystals (CNC) so they can develop a product idea. (It’s been a few years since the last request and I hope that means it’s easier to get access to CNC.)

Regardless, access remains a problem and the European Union has devised a solution which allows open access to nanoparticles and nanocomposites through project Co-Pilot. The announcement was made in a May 10, 2016 news item on Nanowerk (Note: A link has been removed),

“What opportunities does the nanotechnology provide in general, provide nanoparticles for my products and processes?” So far, this question cannot be answered easily. Preparation and modification of nanoparticles and the further processing require special technical infrastructure and complex knowledge. For small and medium businesses the construction of this infrastructure “just on luck” is often not worth it. Even large companies shy away from the risks. As a result many good ideas just stay in the drawer.

A simple and open access to high-class infrastructure for the reliable production of small batches of functionalized nanoparticles and nanocomposites for testing could ease the way towards new nano-based products for chemical and pharmaceutical companies. The European Union has allocated funds for the construction of a number of pilot lines and open-access infrastructure within the framework of the EU project CoPilot.

A May 9, 2016 Fraunhofer-Institut für Silicatforschung press release, which originated the news item, offers greater description,

A simple and open access to high-class infrastructure for the reliable production of small batches of functionalized nanoparticles and nanocomposites for testing could ease the way towards new nano-based products for chemical and pharmaceutical companies. The European Union has allocated funds for the construction of a number of pilot lines and open-access infrastructure within the framework of the EU project CoPilot. A consortium of 13 partners from research and industry, including nanotechnology specialist TNO from the Netherlands and the Fraunhofer Institute for Silicate Research ISC from Wuerzburg, Germany as well as seven nanomaterial manufacturers, is currently setting up the pilot line in Wuerzburg. First, they establish the particle production, modification and compounding on pilot scale based on four different model systems. The approach enables maximum variability and flexibility for the pilot production of various particle systems and composites. Two further open access lines will be established at TNO in Eindhoven and at the Sueddeutsche Kunststoffzentrum SKZ in Selb.

The “nanoparticle kitchen”

Essential elements of the pilot line in Wuerzburg are the particle synthesis in batches up to 100 liters, modification and separation methods such as semi-continuous operating centrifuge and in-line analysis and techniques for the uniform and agglomeration free incorporation of nanoparticles into composites. Dr. Karl Mandel, head of Particle Technology of Fraunhofer ISC, compares the pilot line with a high-tech kitchen: “We provide the top-notch equipment and the star chefs to synthesize a nano menu à la carte as well as nanoparticles according to individual requests. Thus, companies can test their own receipts – or our existing receipts – before they practice their own cooking or set up their nano kitchen.”

In the future, the EU project offers companies a contact point if they want to try their nano idea and require enough material for sampling and estimation of future production costs. This can, on the one hand, minimize the development risk, on the other hand, it maximizes the flexibility and production safety. To give lots of companies the opportunity to influence direction and structure/formation/setup of the nanoparticle kitchen, the project partners will offer open meetings on a regular basis.

I gather Co-Pilot has been offering workshops. The next is in July 2016 according to the press release,

The next workshop in this context takes place at Fraunhofer ISC in Wuerzburg, 7h July 2016. The partners present the pilot line and the first results of the four model systems – double layered hydroxide nanoparticle polymer composites for flame inhibiting fillers, titanium dioxide nanoparticles for high refractive index composites, magnetic particles for innovative catalysts and hollow silica composites for anti-glare coatings. Interested companies can find more information about the upcoming workshop on the website of the project www.h2020copilot.eu and on the website of Fraunhofer ISC www.isc.fraunhofer.de that hosts the event.

I tracked down a tiny bit more information about the July 2016 workshop in a May 2, 2016 Co-Pilot press release,

On July 7 2016, the CoPilot project partners give an insight view of the many new functionalization and applications of tailored nanoparticles in the workshop “The Nanoparticle Kitchen – particles und functions à la carte”, taking place in Wuerzburg, Germany. Join the Fraunhofer ISC’s lab tour of the “Nanoparticle Kitchen”, listen to the presentations of research institutes and industry and discuss your ideas with experts. Nanoparticles offer many options for today’s and tomorrow’s products.

More about program and registration soon on this [CoPilot] website!

I wonder if they’re considering this open access to nanoparticles and nanocomposites approach elsewhere?

Mass production of nanoparticles?

With all the years of nanotechnology and nanomaterials research it seems strange that mass production of nanoparticles is still very much in the early stages as a Feb. 24, 2016 news item on phys.org points out,

Nanoparticles – tiny particles 100,000 times smaller than the width of a strand of hair – can be found in everything from drug delivery formulations to pollution controls on cars to HD TV sets. With special properties derived from their tiny size and subsequently increased surface area, they’re critical to industry and scientific research.

They’re also expensive and tricky to make.

Now, researchers at USC [University of Southern California] have created a new way to manufacture nanoparticles that will transform the process from a painstaking, batch-by-batch drudgery into a large-scale, automated assembly line.

A Feb. 24, 2016 USC news release (also on EurekAlert) by Robert Perkins, which originated the news item, offers additional insight,

Consider, for example, gold nanoparticles. They have been shown to easily penetrate cell membranes without causing any damage — an unusual feat given that most penetrations of cell membranes by foreign objects can damage or kill the cell. Their ability to slip through the cell’s membrane makes gold nanoparticles ideal delivery devices for medications to healthy cells or fatal doses of radiation to cancer cells.

However, a single milligram of gold nanoparticles currently costs about $80 (depending on the size of the nanoparticles). That places the price of gold nanoparticles at $80,000 per gram while a gram of pure, raw gold goes for about $50.

“It’s not the gold that’s making it expensive,” Malmstadt [Noah Malmstadt of the USC Viterbi School of Engineering] said. “We can make them, but it’s not like we can cheaply make a 50-gallon drum full of them.”

A fluid situation

At this time, the process of manufacturing a nanoparticle typically involves a technician in a chemistry lab mixing up a batch of chemicals by hand in traditional lab flasks and beakers.

The new technique used by Brutchey [Richard Brutchey of the USC Dornsife College of Letters, Arts and Sciences] and Malmstadt instead relies on microfluidics — technology that manipulates tiny droplets of fluid in narrow channels.

“In order to go large scale, we have to go small,” Brutchey said.

Really small.

The team 3-D printed tubes about 250 micrometers in diameter, which they believe to be the smallest, fully enclosed 3-D printed tubes anywhere. For reference, your average-sized speck of dust is 50 micrometers wide.

They they built a parallel network of four of these tubes, side-by-side, and ran a combination of two nonmixing fluids (like oil and water) through them. As the two fluids fought to get out through the openings, they squeezed off tiny droplets. Each of these droplets acted as a micro-scale chemical reactor in which materials were mixed and nanoparticles were generated. Each microfluidic tube can create millions of identical droplets that perform the same reaction.

This sort of system has been envisioned in the past, but it hasn’t been able to be scaled up because the parallel structure meant that if one tube got jammed, it would cause a ripple effect of changing pressures along its neighbors, knocking out the entire system. Think of it like losing a single Christmas light in one of the old-style strands — lose one and you lose them all.

Brutchey and Malmstadt bypassed this problem by altering the geometry of the tubes themselves, shaping the junction between the tubes such that the particles come out a uniform size and the system is immune to pressure changes.

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

Flow invariant droplet formation for stable parallel microreactors by Carson T. Riche, Emily J. Roberts, Malancha Gupta, Richard L. Brutchey & Noah Malmstadt. Nature Communications 7, Article number: 10780 doi:10.1038/ncomms10780 Published 23 February 2016

This is an open access paper.