Tag Archives: cancer

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.

How many nanoparticle-based drugs does it take to kill a cancer tumour? More than 1%

According to an April 27, 2016 news item on Nanowerk researchers at the University of Toronto (Canada) along with their collaborators in the US (Harvard Medical School) and Japan (University of Tokyo) have determined that less than 1% of nanoparticle-based drugs reach their intended destination (Note: A link has been removed),

Targeting cancer cells for destruction while leaving healthy cells alone — that has been the promise of the emerging field of cancer nanomedicine. But a new meta-analysis from U of T’s [University of Toronto] Institute of Biomaterials & Biomedical Engineering (IBBME) indicates that progress so far has been limited and new strategies are needed if the promise is to become reality.

“The amount of research into using engineered nanoparticles to deliver cancer drugs directly to tumours has been growing steadily over the last decade, but there are very few formulations used in patients. The question is why?” says Professor Warren Chan (IBBME, ChemE, MSE), senior author on the review paper published in Nature Reviews Materials (“Analysis of nanoparticle delivery to tumours”). “We felt it was time to look at the field more closely.”

An April 25, 2016 U of T news release, which originated the news item, details the research,

Chan and his co-authors analysed 117 published papers that recorded the delivery efficiency of various nanoparticles to tumours — that is, the percentage of injected nanoparticles that actually reach their intended target. To their surprise, they found that the median value was about 0.7 per cent of injected nanoparticles reaching their targets, and that this number has not changed for the last ten years. “If the nanoparticles do not get delivered to the tumour, they cannot work as designed for many nanomedicines,” says Chan.

Even more surprising was that altering nanoparticles themselves made little difference in the net delivery efficiency. “Researchers have tried different materials and nanoparticle sizes, different surface coatings, different shapes, but all these variations lead to no difference, or only small differences,” says Stefan Wilhelm, a post-doctoral researcher in Chan’s lab and lead author of the paper. “These results suggest that we have to think more about the biology and the mechanisms that are involved in the delivery process rather than just changing characteristics of nanoparticles themselves.”

Wilhelm points out that nanoparticles do have some advantages. Unlike chemotherapy drugs which go everywhere in the body, drugs delivered by nanoparticles accumulate more in some organs and less in others. This can be beneficial: for example, one current treatment uses nanoparticles called liposomes to encapsulate the cancer drug doxorubicin.

This encapsulation reduces the accumulation of doxorubicin in the heart, thereby reducing cardiotoxicity compared with administering the drug on its own.

Unfortunately, the majority of injected nanoparticles, including liposomes, end up in the liver, spleen and kidneys, which is logical since the job of these organs is to clear foreign substances and poisons from the blood. This suggests that in order to prevent nanoparticles from being filtered out of the blood before they reach the target tumour, researchers may have to control the interactions of those organs with nanoparticles.

It may be that there is an optimal particle surface chemistry, size, or shape required to access each type of organ or tissue.  One strategy the authors are pursuing involves engineering nanoparticles that can dynamically respond to conditions in the body by altering their surfaces or other properties, much like proteins do in nature. This may help them to avoid being filtered out by organs such as the liver, but at the same time to have the optimal properties needed to enter tumors.

More generally, the authors argue that, in order to increase nanoparticle delivery efficiency, a systematic and coordinated long-term strategy is necessary. To build a strong foundation for the field of cancer nanomedicine, researchers will need to understand a lot more about the interactions between nanoparticles and the body’s various organs than they do today. To this end, Chan’s lab has developed techniques  to visualize these interactions across whole organs using 3D optical microscopy, a study published in ACS Nano this week.

In addition to this, the team has set up an open online database, called the Cancer Nanomedicine Repository that will enable the collection and analysis of data on nanoparticle delivery efficiency from any study, no matter where it is published. The team has already uploaded the data gathered for the latest paper, but when the database goes live in June, researchers from all over the world will be able to add their data and conduct real-time analysis for their particular area of interest.

“It is a big challenge to collect and find ways to summarize data from a decade of research but this article will be immensely useful to researchers in the field,” says Professor Julie Audet (IBBME), a collaborator on the study.

Wilhelm says there is a long way to go in order to improve the clinical translation of cancer nanomedicines, but he’s optimistic about the results. “From the first publication on liposomes in 1965 to when they were first approved for use in treating cancer, it took 30 years,” he says. “In 2016, we already have a lot of data, so there’s a chance that the translation of new cancer nanomedicines for clinical use could go much faster this time. Our meta-analysis provides a ‘reality’ check of the current state of cancer nanomedicine and identifies the specific areas of research that need to be investigated to ensure that there will be a rapid clinical translation of nanomedicine developments.”

I made time to read this paper,

Analysis of nanoparticle delivery to tumours by Stefan Wilhelm, Anthony J. Tavares, Qin Dai, Seiichi Ohta, Julie Audet, Harold F. Dvorak, & Warren C. W. Chan. Nature Reviews Materials 1, Article number: 16014 (2016  doi:10.1038/natrevmats.2016.14 Published online: 26 April 2016

It appears to be open access.

The paper is pretty accessible but it does require that you have some tolerance for your own ignorance (assuming you’re not an expert in this area) and time. If you have both, you will find a good description of the various pathways scientists believe nanoparticles take to enter a tumour. In short, they’re not quite sure how nanoparticles gain entry. As well, there are discussions of other problems associated with the field such as producing enough nanoparticles for general usage.

More than an analysis, there’s also a proposed plan for future action (from Analysis of nanoparticle delivery to tumours ),

UofT_30yrCancerMedicine

Current research in using nanoparticles in vivo has focused on innovative design and demonstration of utility of these nanosystems for imaging and treating cancer. The poor clinical translation has encouraged the researchers in the field to investigate the effect of nanoparticle design (for example, size, shape and surface chemistry) on its function and behaviour in the body in the past 10 years. From a cancer-targeting perspective, we do not believe that nanoparticles will be successfully translated to human use if the current ‘research paradigm’ of nanoparticle targeting continues because the delivery efficiency is too low. We propose a long-term strategy to increase the delivery efficiency and enable nanoparticles to be translated to patient care in a cost-effective manner from the research stage. A foundation for the field will be built by obtaining a detailed view of nanoparticle–organ interaction during nanoparticle transport to the tumour, using computational strategies to organize and simulate the results and the development of new tools to assess nanoparticle delivery. In addition, we propose that these results should be collected in a central database to allow progress in the field to be monitored and correlations to be established. A 30-year strategy was proposed and seemed to be a reasonable time frame because the first liposome system was reported in 1965 (Ref. 122) and the first liposome formulation (Doxil) was approved by the US Food and Drug Administration (FDA) in 1995 (Refs 91,92). This 30-year time frame may be shortened as a research foundation has already been established but only if the community can parse the immense amount of currently published data. NP, nanoparticle.

Another paper was mentioned in the news release,

Three-Dimensional Optical Mapping of Nanoparticle Distribution in Intact Tissues by Shrey Sindhwani, Abdullah Muhammad Syed, Stefan Wilhelm, Dylan R Glancy, Yih Yang Chen, Michael Dobosz, and Warren C.W. Chan.ACS Nano, Just Accepted Manuscript Publication Date (Web): April 21, 2016 DOI: 10.1021/acsnano.6b01879

Copyright © 2016 American Chemical Society

This paper is behind a paywall.

Finally, Melanie Ward in an April 26, 2016 article for Science News Hub has another approach to describing the research. Oddly, she states this,

However, the study warns about the lack of efficiency despite major economic investments (more than one billion dollars in the US in the past decade).

She’s right; the US has spent more than $1B in the last decade. In fact, they’ve allocated over $1B every year to the National Nanotechnology Initiative (NNI) for almost two decades for a total of more than $20B. You might want to apply some caution when reading. BTW, I think that’s a wise approach for everything you read including the blog postings here.

Vote for* winner for Generation Nano: Small Science, Superheroes

The US National Science Foundation’s (NSF) contest “Generation Nano: Small Science, Superheroes” for high school students has whittled down the entries to three finalists and bringing them to Washington, DC where the winner will announced at the 2016 USA Science & Engineering Festival (April 16 – 17, 2016) according to a March 30, 2016 NSF news release,

The National Science Foundation (NSF) today announced the names of three finalists in its Generation Nano: Small Science, Superheroes competition, sponsored by NSF and its National Nanotechnology Initiative (NNI) and supported by many, including superhero legend Stan Lee.

High school students Madeleine Chang from Bergen County Academies in New Jersey, Vuong Mai from Martha Ellen Stilwell School of the Arts in Georgia and Eric Liu from Thomas Jefferson High School for Science and Technology in Virginia will come to Washington, D.C., to display their comics and compete for prizes at the 2016 USA Science & Engineering Festival in mid-April.

The competition drew submissions from all over the country. All responded to the call to think big — or in this case small — and use nanotechnology to empower their own original superheroes. Chang’s hero “Radio Blitz” disposes of local waste. Mai’s protector “Nine” dons a Nanosuit for strength to save a kidnapping victim. And Liu’s “Nanoman” fights the malignant crab-monster, “Cancer.”

“These three finalists tell a great story — all while they exemplify the combination of a sound technical basis for use of nanotechnology and artistic presentation,” said Lisa Friedersdorf, deputy director of the National Nanotechnology Coordination Office. “I think these comics will inspire other students to learn more about what is possible with nanotechnology.”

When it comes to applications for nanotechnology, “The possibilities abound,” said Mihail C. Roco, NSF senior advisor for science and engineering and key architect of NNI.

“Since these high school students were born, more discoveries have come from nanotechnology than any other field of science, with its discoveries penetrating all aspects of society — new industries, medicine, agriculture and the management of natural resources,” Roco said. “It is so exciting that these kids are getting in on the ground floor of progress. The competition inspires young people to dream high and create solutions in a way that may change their lives and those around them. We need this new talent; the future of emerging technologies, including nanotechnology depends on it.”

Those of us who cannot attend the festival, can vote online,

And remember to vote for your favorite from April 7 to 15.

*ETA March 31, 2016 at 1115 hours PDT: The vote link from the news release does not seem to be operational presumably since we the voting period doesn’t start until April 7, 2016.

Congratulations to the three finalists!

*’or’ switched to ‘for’  in the headline at 1110 hours PDT on March 31, 2016.

Chemicals that slow biological aging in yeast might help humans too

A March 15, 2016 Concordia University (Montréal, Canada) news release (also on EurekAlert) describes research that may slow the aging process (Note: Links have been removed),

Even though the search for the Fountain of Youth dates back to the ancient Greeks, the quest to live forever continues today. Indeed, it has been said that the ability to slow the aging process would be the most important medical discovery in the modern era.

A new study published in the journal Oncotarget by researchers from Concordia and the Quebec-based biotech company Idunn Technologies may have uncovered an important factor: plant extracts containing the six best groups of anti-aging molecules ever seen.

For the study, the research team combed through Idunn Technologies’ extensive biological library, conducting more than 10,000 trials to screen for plant extracts that would increase the chronological lifespan of yeast.

Why yeast? Cellularly speaking, aging progresses similarly in both yeast and humans. It’s the best cellular model to understand how the anti-aging process takes place.

“In total, we found six new groups of molecules that decelerate the chronological aging of yeast,” says Vladimir Titorenko, the study’s senior author and a professor in the Department of Biology at Concordia. He carried out the study with a group of Concordia students and Éric Simard, the founder of Idunn Technologies, which is named for the goddess of rejuvenation in Norse mythology.

This has important implications not only for slowing the aging process, but also for preventing certain diseases associated with aging, including cancer.

“Rather than focus on curing the individual disease, interventions on the molecular processes of aging can simultaneously delay the onset and progression of most age-related disorders. This kind of intervention is predicted to have a much larger effect on healthy aging and life expectancy than can be attained by treating individual diseases,” says Simard, who notes that these new molecules will soon be available in commercial products.

“These results also provide new insights into mechanisms through which chemicals extracted from certain plants can slow biological aging,” says Titorenko.

One of these groups of molecules is the most potent longevity-extending pharmacological intervention yet described in scientific literature: a specific extract of willow bark.

Willow bark was commonly used during the time of Hippocrates, when people were advised to chew on it to relieve pain and fever. The study showed that it increases the average and maximum chronological lifespan of yeast by 475 per cent and 369 per cent, respectively. This represents a much greater effect than rapamycin and metformin, the two best drugs known for their anti-aging effects.

“These six extracts have been recognized as non-toxic by Health Canada, and already exhibit recognized health benefits in humans,” says Simard.

“But first, more research must be done. That’s why Idunn Technologies is collaborating with four other universities for six research programs, to go beyond yeast, and work with an animal model of aging, as well as two cancer models.”

A rather interesting image was included with the news release,

The Fountain of Youth, a 1546 painting by Lucas Cranach the Elder. Courtesy: Concordia University

The Fountain of Youth, a 1546 painting by Lucas Cranach the Elder. Courtesy: Concordia University

There’s also this,

An extract of willow bark has shown to be one of the most potent longevity-extending pharmacological interventions yet described in scientific literature. Courtesy: Concordia University

An extract of willow bark has shown to be one of the most potent longevity-extending pharmacological interventions yet described in scientific literature. Courtesy: Concordia University

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

Discovery of plant extracts that greatly delay yeast chronological aging and have different effects on longevity-defining cellular processes by Vicky Lutchman, Younes Medkour, Eugenie Samson, Anthony Arlia-Ciommo, Pamela Dakik, Berly Cortes, Rachel Feldman, Sadaf Mohtashami, Mélissa McAuley, Marisa Chancharoen, Belise Rukundo, Éric Simard, Vladimir I. Titorenko. DOI: 10.18632/oncotarget.7665 Published: February 24, 2016

This appears to be an open access paper.

You can find out more about Idunn Technologies here but you will need French language reading skills as the English language version of the site is not yet available.