Tag Archives: cancer

Sniffing out disease (Na-Nose)

The ‘artificial nose’ is not a newcomer to this blog. The most recent post prior to this is a March 15, 2016 piece about Disney using an artificial nose for art conservation. Today’s (Jan. 9, 2016) piece concerns itself with work from Israel and ‘sniffing out’ disease, according to a Dec. 30, 2016 news item in Sputnik News,

A team from the Israel Institute of Technology has developed a device that from a single breath can identify diseases such as multiple forms of cancer, Parkinson’s disease, and multiple sclerosis. While the machine is still in the experimental stages, it has a high degree of promise for use in non-invasive diagnoses of serious illnesses.

The international team demonstrated that a medical theory first proposed by the Greek physician Hippocrates some 2400 years ago is true, certain diseases leave a “breathprint” on the exhalations of those afflicted. The researchers created a prototype for a machine that can pick up on those diseases using the outgoing breath of a patient. The machine, called the Na-Nose, tests breath samples for the presence of trace amounts of chemicals that are indicative of 17 different illnesses.

A Dec. 22, 2016 Technion Israel Institute of Technology press release offers more detail about the work,

An international team of 56 researchers in five countries has confirmed a hypothesis first proposed by the ancient Greeks – that different diseases are characterized by different “chemical signatures” identifiable in breath samples. …

Diagnostic techniques based on breath samples have been demonstrated in the past, but until now, there has not been scientific proof of the hypothesis that different and unrelated diseases are characterized by distinct chemical breath signatures. And technologies developed to date for this type of diagnosis have been limited to detecting a small number of clinical disorders, without differentiation between unrelated diseases.

The study of more than 1,400 patients included 17 different and unrelated diseases: lung cancer, colorectal cancer, head and neck cancer, ovarian cancer, bladder cancer, prostate cancer, kidney cancer, stomach cancer, Crohn’s disease, ulcerative colitis, irritable bowel syndrome, Parkinson’s disease (two types), multiple sclerosis, pulmonary hypertension, preeclampsia and chronic kidney disease. Samples were collected between January 2011 and June 2014 from in 14 departments at 9 medical centers in 5 countries: Israel, France, the USA, Latvia and China.

The researchers tested the chemical composition of the breath samples using an accepted analytical method (mass spectrometry), which enabled accurate quantitative detection of the chemical compounds they contained. 13 chemical components were identified, in different compositions, in all 17 of the diseases.

According to Prof. Haick, “each of these diseases is characterized by a unique fingerprint, meaning a different composition of these 13 chemical components.  Just as each of us has a unique fingerprint that distinguishes us from others, each disease has a chemical signature that distinguishes it from other diseases and from a normal state of health. These odor signatures are what enables us to identify the diseases using the technology that we developed.”

With a new technology called “artificially intelligent nanoarray,” developed by Prof. Haick, the researchers were able to corroborate the clinical efficacy of the diagnostic technology. The array enables fast and inexpensive diagnosis and classification of diseases, based on “smelling” the patient’s breath, and using artificial intelligence to analyze the data obtained from the sensors. Some of the sensors are based on layers of gold nanoscale particles and others contain a random network of carbon nanotubes coated with an organic layer for sensing and identification purposes.

The study also assessed the efficiency of the artificially intelligent nanoarray in detecting and classifying various diseases using breath signatures. To verify the reliability of the system, the team also examined the effect of various factors (such as gender, age, smoking habits and geographic location) on the sample composition, and found their effect to be negligible, and without impairment on the array’s sensitivity.

“Each of the sensors responds to a wide range of exhalation components,” explain Prof. Haick and his previous Ph.D student, Dr. Morad Nakhleh, “and integration of the information provides detailed data about the unique breath signatures characteristic of the various diseases. Our system has detected and classified various diseases with an average accuracy of 86%.

This is a new and promising direction for diagnosis and classification of diseases, which is characterized not only by considerable accuracy but also by low cost, low electricity consumption, miniaturization, comfort and the possibility of repeating the test easily.”

“Breath is an excellent raw material for diagnosis,” said Prof. Haick. “It is available without the need for invasive and unpleasant procedures, it’s not dangerous, and you can sample it again and again if necessary.”

Here’s a schematic of the study, which the researchers have made available,

Diagram: A schematic view of the study. Two breath samples were taken from each subject, one was sent for chemical mapping using mass spectrometry, and the other was analyzed in the new system, which produced a clinical diagnosis based on the chemical fingerprint of the breath sample. Courtesy: Tech;nion

There is also a video, which covers much of the same ground as the press release but also includes information about the possible use of the Na-Nose technology in the European Union’s SniffPhone project,

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

Diagnosis and Classification of 17 Diseases from 1404 Subjects via Pattern Analysis of Exhaled Molecules by Morad K. Nakhleh, Haitham Amal, Raneen Jeries, Yoav Y. Broza, Manal Aboud, Alaa Gharra, Hodaya Ivgi, Salam Khatib, Shifaa Badarneh, Lior Har-Shai, Lea Glass-Marmor, Izabella Lejbkowicz, Ariel Miller, Samih Badarny, Raz Winer, John Finberg, Sylvia Cohen-Kaminsky, Frédéric Perros, David Montani, Barbara Girerd, Gilles Garcia, Gérald Simonneau, Farid Nakhoul, Shira Baram, Raed Salim, Marwan Hakim, Maayan Gruber, Ohad Ronen, Tal Marshak, Ilana Doweck, Ofer Nativ, Zaher Bahouth, Da-you Shi, Wei Zhang, Qing-ling Hua, Yue-yin Pan, Li Tao, Hu Liu, Amir Karban, Eduard Koifman, Tova Rainis, Roberts Skapars, Armands Sivins, Guntis Ancans, Inta Liepniece-Karele, Ilze Kikuste, Ieva Lasina, Ivars Tolmanis, Douglas Johnson, Stuart Z. Millstone, Jennifer Fulton, John W. Wells, Larry H. Wilf, Marc Humbert, Marcis Leja, Nir Peled, and Hossam Haick. ACS Nano, Article ASAP DOI: 10.1021/acsnano.6b04930 Publication Date (Web): December 21, 2016

Copyright © 2017 American Chemical Society

This paper appears to be open access.

As for SniffPhone, they’re hoping that Na-Nose or something like it will allow them to modify smartphones in a way that will allow diseases to be detected.

I can’t help wondering who will own the data if your smartphone detects a disease. If you think that’s an idle question, here’s an excerpt from Sue Halpern’s Dec. 22, 2016 review of two books (“Weapons of Math Destruction: How Big Data Increases Inequality and Threatens Democracy” by Cathy O’Neil and “Virtual Competition: The Promise and Perils of the Algorithm-Driven Economy” by Ariel Ezrachi and Maurice E. Stucke) for the New York Times Review of Books,

We give our data away. We give it away in drips and drops, not thinking that data brokers will collect it and sell it, let alone that it will be used against us. There are now private, unregulated DNA databases culled, in part, from DNA samples people supply to genealogical websites in pursuit of their ancestry. These samples are available online to be compared with crime scene DNA without a warrant or court order. (Police are also amassing their own DNA databases by swabbing cheeks during routine stops.) In the estimation of the Electronic Frontier Foundation, this will make it more likely that people will be implicated in crimes they did not commit.

Or consider the data from fitness trackers, like Fitbit. As reported in The Intercept:

During a 2013 FTC panel on “Connected Health and Fitness,” University of Colorado law professor Scott Peppet said, “I can paint an incredibly detailed and rich picture of who you are based on your Fitbit data,” adding, “That data is so high quality that I can do things like price insurance premiums or I could probably evaluate your credit score incredibly accurately.”

Halpern’s piece is well worth reading in its entirety.

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).

Liquid biopsy chip that uses carbon nanotubes in place of microfluidics

They’re calling this a breakthrough technology in a Dec. 15, 2016 news item on ScienceDaily,

A chip developed by mechanical engineers at Worcester Polytechnic Institute (WPI) [UK] can trap and identify metastatic cancer cells in a small amount of blood drawn from a cancer patient. The breakthrough technology uses a simple mechanical method that has been shown to be more effective in trapping cancer cells than the microfluidic approach employed in many existing devices.

The WPI device uses antibodies attached to an array of carbon nanotubes at the bottom of a tiny well. Cancer cells settle to the bottom of the well, where they selectively bind to the antibodies based on their surface markers (unlike other devices, the chip can also trap tiny structures called exosomes produced by cancers cells). This “liquid biopsy,” described in a recent issue of the journal Nanotechnology, could become the basis of a simple lab test that could quickly detect early signs of metastasis and help physicians select treatments targeted at the specific cancer cells identified.

A Dec. 15, 2016 WPI press release (also on EurekAlert), which originated the news item, explains the breakthrough in more detail (Note: Links have been removed),

Metastasis is the process by which a cancer can spread from one organ to other parts of the body, typically by entering the bloodstream. Different types of tumors show a preference for specific organs and tissues; circulating breast cancer cells, for example, are likely to take root in bones, lungs, and the brain. The prognosis for metastatic cancer (also called stage IV cancer) is generally poor, so a technique that could detect these circulating tumor cells before they have a chance to form new colonies of tumors at distant sites could greatly increase a patient’s survival odds.

“The focus on capturing circulating tumor cells is quite new,” said Balaji Panchapakesan, associate professor of mechanical engineering at WPI and director of the Small Systems Laboratory. “It is a very difficult challenge, not unlike looking for a needle in a haystack. There are billions of red blood cells, tens of thousands of white blood cells, and, perhaps, only a small number of tumor cells floating among them. We’ve shown how those cells can be captured with high precision.”

The device developed by Panchapakesan’s team includes an array of tiny elements, each about a tenth of an inch (3 millimeters) across. Each element has a well, at the bottom of which are antibodies attached to carbon nanotubes. Each well holds a specific antibody that will bind selectively to one type of cancer cell type, based on genetic markers on its surface. By seeding elements with an assortment of antibodies, the device could be set up to capture several different cancer cells types using a single blood sample. In the lab, the researchers were able to fill a total of 170 wells using just under 0.3 fluid ounces (0.85 milliliter) of blood. Even with that small sample, they captured between one and a thousand cells per device, with a capture efficiency of between 62 and 100 percent.

In a paper published in the journal Nanotechnology [“Static micro-array isolation, dynamic time series classification, capture and enumeration of spiked breast cancer cells in blood: the nanotube–CTC chip”], Panchapakesan’s team, which includes postdoctoral researcher Farhad Khosravi, the paper’s lead author, and researchers at the University of Louisville and Thomas Jefferson University, describe a study in which antibodies specific for two markers of metastatic breast cancer, EpCam and Her2, were attached to the carbon nanotubes in the chip. When a blood sample that had been “spiked” with cells expressing those markers was placed on the chip, the device was shown to reliably capture only the marked cells.

In addition to capturing tumor cells, Panchapakesan says the chip will also latch on to tiny structures called exosomes, which are produced by cancers [sic] cells and carry the same markers. “These highly elusive 3-nanometer structures are too small to be captured with other types of liquid biopsy devices, such as microfluidics, due to shear forces that can potentially destroy them,” he noted. “Our chip is currently the only device that can potentially capture circulating tumor cells and exosomes directly on the chip, which should increase its ability to detect metastasis. This can be important because emerging evidence suggests that tiny proteins excreted with exosomes can drive reactions that may become major barriers to effective cancer drug delivery and treatment.”

Panchapakesan said the chip developed by his team has additional advantages over other liquid biopsy devices, most of which use microfluidics to capture cancer cells. In addition to being able to capture circulating tumor cells far more efficiently than microfluidic chips (in which cells must latch onto anchored antibodies as they pass by in a stream of moving liquid), the WPI device is also highly effective in separating cancer cells from the other cells and material in the blood through differential settling.

While the initial tests with the chip have focused on breast cancer, Panchapakesan says the device could be set up to detect a wide range of tumor types, and plans are already in the works for development of an advanced device as well as testing for other cancer types, including lung and pancreas cancer. He says he envisions a day when a device like his could be employed not only for regular follow ups for patients who have had cancer, but in routine cancer screening.

“Imagine going to the doctor for your yearly physical,” he said. “You have blood drawn and that one blood sample can be tested for a comprehensive array of cancer cell markers. Cancers would be caught at their earliest stage and other stages of development, and doctors would have the necessary protein or genetic information from these captured cells to customize your treatment based on the specific markers for your cancer. This would really be a way to put your health in your own hands.”

“White blood cells, in particular, are a problem, because they are quite numerous in blood and they can be mistaken for cancer cells,” he said. “Our device uses what is called a passive leukocyte depletion strategy. Because of density differences, the cancer cells tend to settle to the bottom of the wells (and this only happens in a narrow window), where they encounter the antibodies. The remainder of the blood contents stays at the top of the wells and can simply be washed away.”

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

Static micro-array isolation, dynamic time series classification, capture and enumeration of spiked breast cancer cells in blood: the nanotube–CTC chip by Farhad Khosravi, Patrick J Trainor, Christopher Lambert, Goetz Kloecker, Eric Wickstrom, Shesh N Rai, and Balaji Panchapakesan. Nanotechnology, Volume 27, Number 44 DOI http://dx.doi.org/10.1088/0957-4484/27/44/44LT03 Published 29 September 2016

© 2016 IOP Publishing Ltd

This paper is open access.

A ‘vascular running of the bulls’; nanoparticles in your bloodstream

An Oct. 5, 2016 news item on phys.org announces research into how nanoparticles behave in the bloodstream (Note: A link has been removed),

Researchers at the University of Connecticut have uncovered new information about how particles behave in our bloodstream, an important advancement that could help pharmaceutical scientists develop more effective cancer drugs.

Making sure cancer medications reach the leaky blood vessels surrounding most tumor sites is one of the critical aspects of treatment and drug delivery. While surface chemistry, molecular interactions, and other factors come into play once drug-carrying particles arrive at a tumor, therapeutic medication doesn’t do very much good if it never reaches its intended target.

Anson Ma, an assistant professor of chemical and biomolecular engineering at UConn, used a microfluidic channel device to observe, track, and measure how individual particles behaved in a simulated blood vessel.

The research team’s goal: to learn more about the physics influencing a particle’s behavior as it travels in our blood and to determine which particle size might be the most effective for delivering drugs to their targets. The team’s experimental findings mark the first time such quantitative data has been gathered. …

“Even before particles reach a target site, you have to worry about what is going to happen with them after they get injected into the bloodstream,” Ma says. “Are they going to clump together? How are they going to move around? Are they going to get swept away and flushed out of our bodies?”

Using a high-powered fluorescence microscope in UConn’s Complex Fluids Lab, Ma was able to observe particles being carried along in the simulated blood vessel in what could be described as a vascular Running of the Bulls [emphasis mine]. Red blood cells race through the middle of the channel as the particles – highlighted under the fluorescent light – get carried along in the rush, bumping and bouncing off the blood cells until they are pushed to open spaces – called the cell-free layer – along the vessel’s walls.

Nanocarrier particles injected into the bloodstream bounce off red and white blood cells and platelets, and are pushed toward the blood vessel walls. This physical interaction, measured and quantified for the first time by engineering professor Anson Ma’s lab, provides important information for drug developers. (Image courtesy of Anson Ma)

Nanocarrier particles injected into the bloodstream bounce off red and white blood cells and platelets, and are pushed toward the blood vessel walls. This physical interaction, measured and quantified for the first time by engineering professor Anson Ma’s lab, provides important information for drug developers. (Image courtesy of Anson Ma)

An Oct. 4, 2016 University of Connecticut news release, which originated the news item, provides more detail about the research,

What Ma found was that larger particles – the optimum size appeared to be about 2 microns – were most likely to get pushed to the cell-free layer, where their chances of carrying medication into a tumor site are greatest. The research team also determined that 2 microns was the largest size that should be used if particles are going to have any chance of going through the leaky blood vessel walls into the tumor site.

“When it comes to using particles for the delivery of cancer drugs, size matters,” Ma says. “When you have a bigger particle, the chance of it bumping into blood cells is much higher, there are a lot more collisions, and they tend to get pushed to the blood vessel walls.”

The results were somewhat surprising. In preparing their hypothesis, the research team estimated that smaller particles were probably the most effective since they would move the most in collisions with blood cells, much like what happens when a small ball bounces off a larger one. But just the opposite proved true. The smaller particles appeared to skirt through the mass of moving blood cells and were less likely to experience the “trampoline” effect and get bounced to the cell-free layer, says Ma.

Ma proposed the study after talking to a UConn pharmaceutical scientist about drug development at a campus event five years ago.

“We had a great conversation about how drugs are made and then I asked, ‘But how can you be sure where the particles go?’” Ma recalls, laughing. “I’m an engineer. That’s how we think. I was curious. This was an engineering question. So I said, ‘Let’s write a proposal!’”

The proposal was funded by the National Science Foundation’s Early-concept Grants for Exploratory Research or EAGER program, which supports exploratory work in its early stages on untested, but potentially transformative, research ideas or approaches.

Knowing how particles behave in our circulatory system should help improve targeted drug delivery, Ma says, which in turn will further reduce the toxic side effects caused by potent cancer drugs missing their target and impacting the body’s healthy tissue.

The findings were particularly meaningful for Ma, who lost two of his grandparents to cancer and who has long wanted to contribute to cancer research in a meaningful way as an engineer.

Measuring how particles of different sizes move in the bloodstream may also be beneficial in bioimaging, where scientists and doctors want to keep particles circulating in the bloodstream long enough for imaging to occur. In that case, smaller particles would be better, says Ma.

Moving forward, Ma would like to explore other aspects of particle flow in our circulatory system, such as how particles behave when they pass through a constricted area, such as from a blood vessel to a capillary. Capillaries are only about 7 microns in diameter. The average human hair is 100 microns.  Ma says he would like to know how that constricted space might impact particle flow or the ability of particles to accumulate near the vessel walls.

“We have all of this complex geometry in our bodies,” says Ma. “Most people just assume there is no impact when a particle moves from a bigger channel to a smaller channel because they haven’t quantified it. Our plan is to do some experiments to look at this more carefully, building on the work that we just published.”

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

Direct Tracking of Particles and Quantification of Margination in Blood Flow by Erik J. Carbon, Brice H. Bognet, Grant M. Bouchillon, Andrea L. Kadilak, Leslie M. Shor, Michael D. Ward, Anson W.K. Ma. Biophysical Journal Volume 111, Issue 7, p1487–1495, 4 October 2016  DOI: http://dx.doi.org/10.1016/j.bpj.2016.08.026

This paper is behind a paywall.

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.

pH dependent nanoparticle-based contrast agent for MRIs (magnetic resonance images)

This news about a safer and more effective contrast agent for MRIs (magnetic resonance images) developed by Japanese scientists come from a June 6, 2016 article by Heather Zeiger on phys.org. First some explanations,

Magnetic resonance imaging relies on the excitation and subsequent relaxation of protons. In clinical MRI studies, the signal is determined by the relaxation time of the hydrogen protons in water. To get a stronger signal, scientists can use contrast agents to shorten the relaxation time of the protons.

MRI is non-invasive and does not involve radiation, making it a safe diagnostic tool. However, its weak signal makes tumor detection difficult. The ideal contrast agent would select for malignant tumors, making its location and diagnosis much more obvious.

Nanoparticle contrast agents have been of interested because nanoparticles can be functionalized and, as in this study, can contain various metals. Researchers have attempted to functionalize nanoparticles with ligands that attach to chemical factors on the surface of cancer cells. However, cancer cells tend to be compositionally heterogeneous, leading some researchers to look for nanoparticles that respond to differences in pH or redox potential compared to normal cells.

Now for the research,

Researchers from the University of Tokyo, Tokyo Institute of Technology, Kawasaki Institute of Industry Promotion, and the Japan Agency for Quantum and Radiological Science and Technology have developed a contrast agent from calcium phosphate-based nanoparticles that release a manganese ion an acidic environment. …

Peng Mi, Daisuke Kokuryo, Horacio Cabral, Hailiang Wu, Yasuko Terada, Tsuneo Saga, Ichio Aoki, Nobuhiro Nishiyama, and Kazunori Kataoka developed a contrast agent that is comprised of Mn2+– doped CaP nanoparticles with a PEG shell. They reasoned that using CaP nanoparticles, which are known to be pH sensitive, would allow the targeted release of Mn2+ ions in the tumor microenvironment. The tumor microenvironment tends to have a lower pH than the normal regions to rapid cell metabolism in an oxygen-depleted environment. Manganese ions were tested because they are paramagnetic, which makes for a good contrast agent. They also bind to proteins creating a slowly rotating manganese-protein system that results in sharp contrast enhancement.

These results were promising, so Peng Mi, et al. then tested whether the CaPMnPEG contrast agent worked in solid tumors. Because Mn2+ remains confined within the nanoparticle matrix at physiological pH, CaPMnPEG demonstrate a much lower toxicity [emphasis mine] compared to MnCl2. MRI studies showed a tumor-to-normal contrast of 131% after 30 minute, which is much higher than Gd-DTPA [emphasis mine], a clinically approved contrast agent. After an hour, the tumor-to-normal ratio was 160% and remained around 170% for several hours.

Three-dimensional MRI studies of solid tumors showed that without the addition of CaPMnPEG, only blood vessels were visible. However, upon adding CaPMnPEG, the tumor was easily distinguishable. Additionally, there is evidence that excess Mn2+ leaves the plasma after an hour. The contrast signal remained strong for several hours indicating that protein binding rather than Mn2+ concentration is important for signal enhancement.

Finally, tests with metastatic tumors in the liver (C26 colon cancer cells) showed that CaPMnPEG works well in solid organ analysis and is highly sensitive to detecting millimeter-sized micrometastasis [emphasis mine]. Unlike other contrast agents used in the clinic, CaPMnPEG provided a contrast signal that lasted for several hours after injection. After an hour, the signal was enhanced by 25% and after two hours, the signal was enhanced by 39%.

This is exciting stuff. Bravo to the researchers!

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

A pH-activatable nanoparticle with signal-amplification capabilities for non-invasive imaging of tumour malignancy by Peng Mi, Daisuke Kokuryo, Horacio Cabral, Hailiang Wu, Yasuko Terada, Tsuneo Saga, Ichio Aoki, Nobuhiro Nishiyama, & Kazunori Kataoka. Nature Nanotechnology (2016) doi:10.1038/nnano.2016.72 Published online 16 May 2016

This paper is behind a paywall.

Device detects molecules associated with neurodegenerative diseases

It’s nice to get notice of research in South America, an area for which I rarely stumble across any news releases. Brazilian researchers have developed a device that could help diagnose neurodegenerative diseases such as Alzheimer’s and and Parkinson’s as well as some cancers according to a May 20, 2016 news item on Nanotechnology Now,

A biosensor developed by researchers at the National Nanotechnology Laboratory (LNNano) in Campinas, São Paulo State, Brazil, has been proven capable of detecting molecules associated with neurodegenerative diseases and some types of cancer.

The device is basically a single-layer organic nanometer-scale transistor on a glass slide. It contains the reduced form of the peptide glutathione (GSH), which reacts in a specific way when it comes into contact with the enzyme glutathione S-transferase (GST), linked to Parkinson’s, Alzheimer’s and breast cancer, among other diseases. The GSH-GST reaction is detected by the transistor, which can be used for diagnostic purposes.

The project focuses on the development of point-of-care devices by researchers in a range of knowledge areas, using functional materials to produce simple sensors and microfluidic systems for rapid diagnosis.

A May 19, 2016 Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) press release, which originated the news item, provides more detail,

“Platforms like this one can be deployed to diagnose complex diseases quickly, safely and relatively cheaply, using nanometer-scale systems to identify molecules of interest in the material analyzed,” explained Carlos Cesar Bof Bufon, Head of LNNano’s Functional Devices & Systems Lab (DSF) and a member of the research team for the project, whose principal investigator is Lauro Kubota, a professor at the University of Campinas’s Chemistry Institute (IQ-UNICAMP).

In addition to portability and low cost, the advantages of the nanometric biosensor include its sensitivity in detecting molecules, according to Bufon.

“This is the first time organic transistor technology has been used in detecting the pair GSH-GST, which is important in diagnosing degenerative diseases, for example,” he explained. “The device can detect such molecules even when they’re present at very low levels in the examined material, thanks to its nanometric sensitivity.” A nanometer (nm) is one billionth of a meter (10-9 meter), or one millionth of a millimeter.

The system can be adapted to detect other substances, such as molecules linked to different diseases and elements present in contaminated material, among other applications. This requires replacing the molecules in the sensor with others that react with the chemicals targeted by the test, which are known as analytes.

The team is working on paper-based biosensors to lower the cost even further and to improve portability and facilitate fabrication as well as disposal.

The challenge is that paper is an insulator in its usual form. Bufon has developed a technique to make paper conductive and capable of transporting sensing data by impregnating cellulose fibers with polymers that have conductive properties.

The technique is based on in situ synthesis of conductive polymers. For the polymers not to remain trapped on the surface of the paper, they have to be synthesized inside and between the pores of the cellulose fibers. This is done by gas-phase chemical polymerization: a liquid oxidant is infiltrated into the paper, which is then exposed to monomers in the gas phase. A monomer is a molecule of low molecular weight capable of reacting with identical or different molecules of low molecular weight to form a polymer.

The monomers evaporate under the paper and penetrate the pores of the fibers at the submicrometer scale. Inside the pores, they blend with the oxidant and begin the polymerization process right there, impregnating the entire material.

The polymerized paper acquires the conductive properties of the polymers. This conductivity can be adjusted by manipulating the element embedded in the cellulose fibers, depending on the application for which the paper is designed. Thus, the device can be electrically conductive, allowing current to flow without significant losses, or semiconductive, interacting with specific molecules and functioning as a physical, chemical or electrochemical sensor.

There’s no mention of a published paper.

Combining chitosan, agarose, and protein gelatine with clay nanotubes to create scaffolds for tissue engineering

Russian scientists have published work on clay nanotube-bipolymer composite scaffolds according to an April 29, 2016 news item on ScienceDaily,

Scientists combined three biopolymers, chitosan and agarose (polysaccharides), and a protein gelatine, as the materials to produce tissue engineering scaffolds and demonstrated the enhancement of mechanical strength (doubled pick load), higher water uptake and thermal properties in chitosan-gelatine-agarose hydrogels doped with halloysite [a clay mineral and a naturally occurring nanotube].

An April 29, 2016 Kazan Federal University (Russia) press release on EurekAlert, which originated the news item, provides more detail and context,

The fabrication of a prototype tissue having functional properties close to the natural ones is crucial for effective transplantation. Tissue engineering scaffolds are typically used as supports which allow cells to form tissue-like structures essentially required for the correct functioning of the cells under the conditions close to the three-dimensional tissue.

Chitosan, a natural biodegradable and chemically versatile biopolymer, has been effectively used in antibacterial, antifungal, anti-tumour and immunostimulating formulations. To overcome the disadvantages of pure chitosan scaffolds such as mechanical fragility and low biological resistance, chitosan scaffolds are typically doped with other supporting compounds which allow for mechanical strengthening, thus yielding ?omposite biologically resistant scaffolds.

Agarose is a galactose-based backbone polysaccharide isolated from red algae, having remarkable mechanical properties which are useful in the design of tissue engineering scaffolds.

Gelatine is formed from collagen by hydrolysis (breaking the triple-helix structure into single-strand molecules) and has a number of advantages over its precursor. It is less immunogenic compared with collagen and it retains informational signal sequences promoting cell adhesion, migration, differentiation and proliferation.

The surface irregularities of the scaffold pores due to the insoluble nanosized components promote the best adhesion of the cells on scaffold materials, while the nanoparticle fillers increase the composites’ strength. Thus, researchers doped halloysite nanotubes into a chitosan-agarose-gelatine matrix to design the implantable 3D cell scaffolds.

The resulting scaffolds demonstrate the shape memory upon deformation and have the porous structure suitable for cell adhesion and proliferation which is essential for artificial tissue fabrication. Macroscopic observations have confirmed that all the samples of scaffolds exhibited the sponge-like behaviour with the shape memory and shape reconstitution after deformation both in wet and dry states.

The swelling experiments indicated that the addition of halloysite can greatly improve the hydrophilicity and wetting of composite scaffolds. The incorporation of halloysite nanotubes into the scaffolds increases the water uptake and subsequently improves the biocompatibility. The intrinsic properties of halloysite nanotubes can be used for further improving the biocompatibility of scaffolds by the loading and sustained release of different bioactive compounds. This opens the prospect for fabrication of scaffolds with defined properties for directed differentiation of cells on matrixes due to gradual release of differentiation factors.

Experiments on two types of human cancer cells (A549 and Hep3B) show that in vitro cell adhesion and proliferation on the nanocomposites occur without changes in viability and cytoskeleton formation.

Further in vivo biocompatibility and biodegradability evaluation in rats has confirmed that the scaffolds promote the formation of novel blood vessels around the implantation sites. The scaffolds show excellent resorption within six weeks after implantation in rats. Neo-vascularization observed in newly formed connective tissue placed near the scaffold allows for the complete restoration of blood flow.

The results obtained indicate that the halloysite doped scaffolds are biocompatible as demonstrated both in vitro and in vivo. In addition, they confirm the great potential of chitosan-agarose-gelatine nanocomposite porous scaffolds doped with halloysite in tissue engineering with potential for sustained nanotube drug delivery.

For anyone interested about drug delivery and nanoparticles, there’s some interesting research profiled in my April 27, 2016 posting which describes how very few nanoparticles are actually delivered to specific sites.

Getting back to the regular program, here’s a link to and a citation for the paper on scaffolds and clay nanotubes,

Clay nanotube–biopolymer composite scaffolds for tissue engineering by Ekaterina A. Naumenko, Ivan D. Guryanov, Raghuvara Yendluri, Yuri M. Lvova, and Rawil F. Fakhrullin. Nanoscale, 2016,8, 7257-7271 DOI: 10.1039/C6NR00641H First published online 01 Mar 2016

This paper is behind a paywall.

Arbro Pharmaceuticals and its bioavailable curcumin

Curcumin (a constituent of the spice turmeric) is reputed to have health benefits and has been used in traditional medicine in Asia (notably India) for millenia. Recently scientists have been trying to render curcumin more effective which means increasing its bioavailability (my Nov. 7, 2014 posting features some of that research). According to an April 29, 2016 Arbro Pharmaceuticals press release, the goal of increased bioavailability has been reached and a product is now available commercially,

Arbro Pharmaceuticals has launched SNEC30, a patented highly bioavailable self-nanoemulsifying curcumin formulation in the dosage of 30mg.

Curcumin is the active ingredient of turmeric or haldi, which has been widely used in traditional medicine and home remedies in India for hundreds of years.

Clinical research conducted over the last 25 years has shown curcumin to be effective against various diseases like cancer, pain, inflammation, arthritis, ulcers, psoriasis, arteriosclerosis, diabetes and many more pro-inflammatory conditions.

Despite its effectiveness against so many medical conditions, scientists have come to believe that curcumin’s true potential has been limited by its poor bioavailability which is caused by the fact that it has poor solubility and extensive pre-systemic metabolism.

Arbro Pharmaceuticals partnered with Jamia Hamdard University to carry out research and develop a novel formulation, which can overcome curcumin’s poor bioavailability. The development project was jointly funded by Arbro and the Department of Science and Technology, Government of India under its DPRP (Drug and Pharmaceutical Research Programme) scheme.

SNEC30 is the outcome of this joint research and is based on a novel self-nanoemulsifying drug delivery systems (SNEDDS) for which patents have been filed and the US patent has been granted.

“There has been tremendous interest in the therapeutic potential of curcumin but its poor bioavailability was a limiting factor, our research group together with Arbro took the challenge and applied nanotechnology to overcome this limitation and achieve highest ever bioavailability for curcumin,” said Dr. Kanchan Kohli, Asst. Prof, Faculty of Pharmacy, Jamia Hamdard University, who is one of the main developers of the formulation.

Nanotechnology is the engineering of functional systems at the molecular scale (CRN – Centre for Responsible Nanotechnology). The name stems from the fact that the structures are in the nano-metre (10-9 mm) in range. In pharmaceutics, nano-formulations are used for targeted drug-delivery, particularly in cancer therapy. It also finds numerous other applications in medicine.

“Just 30mg of curcumin that is contained in one capsule of SNEC30 has shown higher blood levels than what can be achieved by consuming the curcumin content of 1kg of raw haldi or turmeric,” said Mr. Vijay Kumar Arora, Managing Director, Arbro Pharmaceuticals.

About Arbro Pharmaceuticals:

Arbro Pharmaceuticals is a 30-year-old research oriented company with its own research and development, testing and manufacturing facilities. Arbro has been manufacturing and exporting hundreds of formulations under its own brand name to more than 10 countries.

I am not endorsing this product but if you are interested the SNEC30 website is here. I believe Arbro Pharmaceuticals’ headquarters, the company which produces SNEC30, are located in India.