Tag Archives: cancer

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 ),


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.

Shape-shifting nanoparticles for better chemotherapy from the University of Toronto (Canada)

A research team from the University of Toronto and its shape-shifting nanoparticles are being touted in a Feb. 19, 2016 news item on Nanowerk,

Chemotherapy isn’t supposed to make your hair fall out — it’s supposed to kill cancer cells. A new molecular delivery system created at U of T [University of Toronto] Engineering could help ensure that chemotherapy drugs get to their target while minimizing collateral damage.

Many cancer drugs target fast-growing cells. Injected into a patient, they swirl around in the bloodstream acting on fast-growing cells wherever they find them. That includes tumours, but unfortunately also hair follicles, the lining of your digestive system, and your skin.

U of T Engineering Professor Warren Chan has spent the last decade figuring out how to deliver chemotherapy drugs into tumours — and nowhere else. Now his lab has designed a set of nanoparticles attached to strands of DNA that can change shape to gain access to diseased tissue.

A Feb. 18, 2016 University of Toronto news release (also on EurekAlert), which originated the news item, expands on the theme,

“Your body is basically a series of compartments,” says Chan. “Think of it as a giant house with rooms inside. We’re trying to figure out how to get something that’s outside, into one specific room. One has to develop a map and a system that can move through the house where each path to the final room may have different restrictions such as height and width.”

One thing we know about cancer: no two tumours are identical. Early-stage breast cancer, for example, may react differently to a given treatment than pancreatic cancer, or even breast cancer at a more advanced stage. Which particles can get inside which tumours depends on multiple factors such as the particle’s size, shape and surface chemistry.

Chan and his research group have studied how these factors dictate the delivery of small molecules and nanotechnologies to tumours, and have now designed a targeted molecular delivery system that uses modular nanoparticles whose shape, size and chemistry can be altered by the presence of specific DNA sequences.

“We’re making shape-changing nanoparticles,” says Chan. “They’re a series of building blocks, kind of like a LEGO set.” The component pieces can be built into many shapes, with binding sites exposed or hidden. They are designed to respond to biological molecules by changing shape, like a key fitting into a lock.

These shape-shifters are made of minuscule chunks of metal with strands of DNA attached to them. Chan envisions that the nanoparticles will float around harmlessly in the blood stream, until a DNA strand binds to a sequence of DNA known to be a marker for cancer. When this happens, the particle changes shape, then carries out its function: it can target the cancer cells, expose a drug molecule to the cancerous cell, tag the cancerous cells with a signal molecule, or whatever task Chan’s team has designed the nanoparticle to carry out.

“We were inspired by the ability of proteins to alter their conformation — they somehow figure out how to alleviate all these delivery issues inside the body,” says Chan. “Using this idea, we thought, ‘Can we engineer a nanoparticle to function like a protein, but one that can be programmed outside the body with medical capabilities?’”

Applying nanotechnology and materials science to medicine, and particularly to targeted drug delivery, is still a relatively new concept, but one Chan sees as full of promise. The real problem is how to deliver enough of the nanoparticles directly to the cancer to produce an effective treatment.

“Here’s how we look at these problems: it’s like you’re going to Vancouver from Toronto, but no one tells you how to get there, no one gives you a map, or a plane ticket, or a car — that’s where we are in this field,” he says. “The idea of targeting drugs to tumours is like figuring out how to go to Vancouver. It’s a simple concept, but to get there isn’t simple if not enough information is provided.”

“We’ve only scratched the surface of how nanotechnology ‘delivery’ works in the body, so now we’re continuing to explore different details of why and how tumours and other organs allow or block certain things from getting in,” adds Chan.

He and his group plan to apply the delivery system they’ve designed toward personalized nanomedicine — further tailoring their particles to deliver drugs to your precise type of tumour, and nowhere else.

Here are links to and citations for the team’s two published papers,

DNA-controlled dynamic colloidal nanoparticle systems for mediating cellular interaction by Seiichi Ohta, Dylan Glancy, Warren C. W. Chan. Science  19 Feb 2016: Vol. 351, Issue 6275, pp. 841-845 DOI: 10.1126/science.aad4925

Tailoring nanoparticle designs to target cancer based on tumor pathophysiology by Edward A. Sykes, Qin Dai, Christopher D. Sarsons, Juan Chen, Jonathan V. Rocheleau, David M. Hwang, Gang Zheng, David T. Cramb, Kristina D. Rinker, and Warren C. W. Chan. PNAS     doi: 10.1073/pnas.1521265113 published online Feb. 16, 2016.

Both papers are behind paywalls.

Observing nanoparticle therapeutics interact with blood in real time

Sadly, there are no images showing nanoparticle therapeutics interacting with blood or anything else for that matter to illustrate this story but perhaps the insights offered should suffice. From Sept. 15, 2015 news item on Nanowerk,

Researchers at the National University of Singapore (NUS) have developed a technique to observe, in real time, how individual blood components interact and modify advanced nanoparticle therapeutics. The method, developed by an interdisciplinary team consisting clinician-scientist Assistant Professor Chester Lee Drum of the Department of Medicine at the NUS Yong Loo Lin School of Medicine, Professor T. Venky Venkatesan, Director of NUS Nanoscience and Nanotechnology Institute, and Assistant Professor James Kah of the Department of Biomedical Engineering at the NUS Faculty of Engineering, helps guide the design of future nanoparticles to interact in concert with human blood components, thus avoiding unwanted side effects.

A Sept. 15, 2015 NUS press release, which originated the news item, describes the research in more specific detail,

With their small size and multiple functionalities, nanoparticles have attracted intense attention as both diagnostic and drug delivery systems. However, within minutes of being delivered into the bloodstream, nanoparticles are covered with a shell of serum proteins, also known as a protein ‘corona’.

“The binding of serum proteins can profoundly change the behaviour of nanoparticles, at times leading to rapid clearance by the body and a diminished clinical outcome,” said Asst Prof Kah.

Existing methods such as mass spectroscopy and diffusional radius estimation, although useful for studying important nanoparticle parameters, are unable to provide detailed, real-time binding kinetics.

Novel method to understand nano-bio interactions

The NUS team, together with external collaborator Professor Bo Liedberg from the Nanyang Technological University, showed highly reproducible kinetics for the binding between gold nanoparticles and the four most common serum proteins: human serum albumin, fibrinogen, apolipoprotein A-1, and polyclonal IgG.

“What was remarkable about this project was the initiative taken by Abhijeet Patra, my graduate student from NUS Graduate School for Integrative Sciences and Engineering, in conceptualising the problem, and bringing together the various teams in NUS and beyond to make this a successful programme,” said Prof Venkatesan. “The key development is the use of a new technique using surface plasmon resonance (SPR) technology to measure the protein corona formed when common proteins in the bloodstream bind to nanoparticles,” he added.

The researchers first immobilised the gold nanoparticles to the surface of a SPR sensor chip with a linker molecule. The chip was specially modified with an alginate polymer layer which both provided a negative charge and active sites for ligand immobilisation, and prevented non-specific binding. Using a 6 x 6 microfluidic channel array, they studied up to 36 nanoparticle-protein interactions in a single experiment, running test samples alongside experimental controls.

“Reproducibility and reliability have been a bottleneck in the studies of protein coronas,” said Mr Abhijeet Patra. “The quality and reliability of the data depends most importantly upon the design of good control experiments. Our multiplexed SPR setup was therefore key to ensuring the reliability of our data.”

Testing different concentrations of each of the four proteins, the team found that apolipoprotein A-1 had the highest binding affinity for the gold nanoparticle surface, with an association constant almost 100 times that of the lowest affinity protein, polyclonal IgG.

“Our results show that the rate of association, rather than dissociation, is the main determinant of binding with the tested blood components,” said Asst Prof Drum.

The multiplex SPR system was also used to study the effect of modification with polyethylene (PEG), a synthetic polymer commonly used in nanoparticle formulations to prevent protein accumulation. The researchers found that shorter PEG chains (2-10 kilodaltons) are about three to four times more effective than longer PEG chains (20-30 kilodaltons) at preventing corona formation.

“The modular nature of our protocol allows us to study any nanoparticle which can be chemically tethered to the sensing surface,” explained Asst Prof Drum. “Using our technique, we can quickly evaluate a series of nanoparticle-based drug formulations before conducting in vivo studies, thereby resulting in savings in time and money and a reduction of in vivo testing,” he added.

The researchers plan to use the technology to quantitatively study protein corona formation for a variety of nanoparticle formulations, and rationally design nanomedicines for applications in cardiovascular diseases and cancer.

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

Component-Specific Analysis of Plasma Protein Corona Formation on Gold Nanoparticles Using Multiplexed Surface Plasmon Resonance by Abhijeet Patra, Tao Ding, Gokce Engudar, Yi Wang, Michal Marcin Dykas, Bo Liedberg, James Chen Yong Kah, Thirumalai Venkatesan, and Chester Lee Drum. Small  DOI: 10.1002/smll.201501603 Article first published online: 10 SEP 2015

© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

This paper is behind a paywall.

Single molecule nanogold-based probe for photoacoustic Imaging and SERS biosensing

As I understand it, the big deal is that A*STAR (Singapore’s Agency for Science, Rechnology and Research) scientists have found a way to make a single molecule probe do the work of a two-molecule probe when imaging tumours. From a July 29, 2015 news item on Nanowerk (Note: A link has been removed),

An organic dye that can light up cancer cells for two powerful imaging techniques providing complementary diagnostic information has been developed and successfully tested in mice by A*STAR researchers (“Single Molecule with Dual Function on Nanogold: Biofunctionalized Construct for In Vivo Photoacoustic Imaging and SERS Biosensing”).

A July 29, 2015 A*STAR news release, which originated the news item, describes the currently used multimodal imaging technique and provides details about the new single molecule technique,

Imaging tumors is vitally important for cancer research, but each imaging technique has its own limitations for studying cancer in living organisms. To overcome the limitations of individual techniques, researchers typically employ a combination of various imaging methods — a practice known as multimodal imaging. In this way, they can obtain complementary information and hence a more complete picture of cancer.

Two very effective methods for imaging tumors are photoacoustic imaging and surface-enhanced Raman scattering (SERS). Photoacoustic imaging can image deep tissue with a good resolution, whereas SERS detects miniscule amounts of a target molecule. To simultaneously use both photoacoustic imaging and SERS, a probe must produce signals for both imaging modalities.

In multimodal imaging, researchers typically combine probes for each imaging modality into a single two-molecule probe. However, the teams of Malini Olivo at the A*STAR Singapore Bioimaging Consortium and Bin Liu at the A*STAR Institute of Materials Research and Engineering, along with overseas collaborator Ben Zhong Tang from the Hong Kong University of Science and Technology, adopted a different approach — they developed single-molecule probes that can be used for both photoacoustic imaging and SERS. The probes are based on organic cyanine dyes that absorb near-infrared light, which has the advantage of being able to deeply penetrate tissue, enabling tumors deep within the body to be imaged.

Once the team had verified that the probes worked for both imaging modalities, they optimized the performances of the probes by adding gold nanoparticles to them to amplify the SERS signal and by encapsulating them in the polymer polyethylene glycol to stabilize their structures.

The researchers then deployed these optimized probes in live mice. By functionalizing the probes with an antibody that recognizes a tumor cell-surface protein, they were able to use them to target tumors. The scientists found that, in photoacoustic imaging, the tumor-targeted probes produced signals that were roughly three times stronger than those of unmodified probes. Using SERS, the team was also able to monitor the concentrations of the probes in the tumor, spleen and liver in real time with a high degree of sensitivity.

U. S. Dinish, a senior scientist in Olivo’s group, recalls the team’s “surprise at the sensitivity and potential of the nanoconstruct.” He anticipates that the probe could be used to guide surgical removal of tumors.

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

Single Molecule with Dual Function on Nanogold: Biofunctionalized Construct for In Vivo Photoacoustic Imaging and SERS Biosensing by U. S. Dinish, Zhegang Song, Chris Jun Hui Ho, Ghayathri Balasundaram, Amalina Binte Ebrahim Attia, Xianmao Lu, Ben Zhong Tang, Bin Liu, and Malini Olivo. Advanced Functional Materials, Vol 25 Issue 15
pages 2316–2325, April 15, 2015 DOI: 10.1002/adfm.201404341 Article first published online: 11 MAR 2015

© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

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Crowdfund nano spies for cancer

University of Groningen (Netherlands) researcher, Romana Schirhagl, is crowdfunding her development of a new technique (using nanodiamonds) for biomedical research which would allow observation of free radicals in cells. From a June 25, 2015 news item on Nanowerk,

Romana Schirhagl, a researcher at the University Medical Center Groningen, is hoping to garner public support for a new form of cancer research. Schirhagl wants to introduce miniscule diamonds into living cancer cells. Like spies, these nanodiamonds will be on a mission to reveal the secrets of the cell. Schirhagl applies a unique combination of knowledge and techniques from physics, chemistry and medicine in the research. This could form the basis of new and improved cancer drugs.

A June 16, 2015 University of Groningen press release, which originated the news item, provides background information for the research,

The research of Schirhagl and her research group in the department of Biomedical Engineering focuses on the behaviour of free radicals in a cell. These radicals have an important role in the body. They are sometimes extremely useful, as in the immune system, where they help fight bacteria and viruses, but sometimes very harmful, as when they actually harm healthy cells and can cause cancer. As the radicals only exist for a fraction of a second, it is difficult to tell them apart and study them.

New technique

Schirhagl wants to apply a new technique that currently is mainly used in fundamental physics but looks extremely promising for biomedical research. The technique is based on very small diamonds that can ‘sense’ the presence of magnetic fields from the radicals. The nanodiamonds are fluorescent and change in luminosity as a response to their environment. This makes it easier to determine which radicals occur when and how they work. This information should make it possible to improve cancer drugs – which themselves sometimes use free radicals – or even develop new ones.

Unexpectedly, the crowdfunding platform is the University of Groningen’s own. You can find out more about Nano spies here. To date the project has raised over 6,600 Euros towards a goal of 20,000 Euros.

Herbicide nanometric sensor could help diagnose multiple sclerosis

This research into nanometric sensors and multiple sclerosis comes from Brazil. According to a June 23, 2015 news item on Nanowerk (Note: A link has been removed),

The early diagnosis of certain types of cancer, as well as nervous system diseases such as multiple sclerosis and neuromyelitis optica, may soon be facilitated by the use of a nanosensor capable of identifying biomarkers of these pathological conditions (“A Nanobiosensor Based on 4-Hydroxyphenylpyruvate Dioxygenase Enzyme for Mesotrione Detection”).

The nanobiosensor was developed at the Federal University of São Carlos (UFSCar), Sorocaba, in partnership with the São Paulo Federal Institute of Education, Science & Technology (IFSP), Itapetininga, São Paulo State, Brazil. It was originally designed to detect herbicides, heavy metals and other pollutants.

A June 23, 2015 Fundação de Amparo à Pesquisa do Estado de São Paulo news release on EurekAlert, which originated the news item, describes the sensor as it was originally used and explains its new function as a diagnostic tool for multiple sclerosis and other diseases,

“It’s a highly sensitive device, which we developed in collaboration with Alberto Luís Dario Moreau, a professor at IFSP. “We were able to increase sensitivity dramatically by going down to the nanometric scale,” said physicist Fábio de Lima Leite, a professor at UFSCar and the coordinator of the research group.

The nanobiosensor consists of a silicon nitride (Si3N4) or silicon (Si) nanoprobe with a molecular-scale elastic constant and a nanotip coupled to an enzyme, protein or other molecule.

When this molecule touches a target of interest, such as an antibody or antigen, the probe bends as the two molecules adhere. The deflection is detected and measured by the device, enabling scientists to identify the target.

“We started by detecting herbicides and heavy metals. Now we’re testing the device for use in detecting target molecules typical of nervous system diseases, in partnership with colleagues at leading centers of research on demyelinating diseases of the central nervous system”

The migration from herbicide detection to antibody detection was motivated mainly by the difficulty of diagnosing demyelinating diseases, cancer and other chronic diseases before they have advanced beyond an initial stage.

The criteria for establishing a diagnosis of multiple sclerosis or neuromyelitis optica are clinical (supplemented by MRI scans), and patients do not always present with a characteristic clinical picture. More precise diagnosis entails ruling out several other diseases.

The development of nanodevices will be of assistance in identifying these diseases and reducing the chances of false diagnosis.

The procedure can be as simple as placing a drop of the patient’s cerebrospinal fluid on a glass slide and observing its interaction with the nanobiosensor.

“If the interaction is low, we’ll be able to rule out multiple sclerosis with great confidence,” Leite said. “High interaction will indicate that the person is very likely to have the disease.” In this case, further testing would be required to exclude the possibility of a false positive.

“Different nervous system diseases have highly similar symptoms. Multiple sclerosis and neuromyelitis optica are just two examples. Even specialists experience difficulties or take a long time to diagnose them. Our technique would provide a differential diagnostic tool,” Leite said.

The next step for the group is to research biomarkers for these diseases that have not been completely mapped, including antibodies and antigens, among others. The group has begun tests for the detection of head and neck cancer.

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

A Nanobiosensor Based on 4-Hydroxyphenylpyruvate Dioxygenase Enzyme for Mesotrione Detection by P. Soto Garcia, A.L.D Moreau, J.C. Magalhaes Ierich,  A.C Araujo Vig, A.M. Higa, G.S. Oliveira, F. Camargo Abdalla, M. Hausen, & F.L. Leite. Sensors Journal, IEEE  (Volume:15 ,  Issue: 4) pp. 2106 – 2113 Date of Publication: 20 November 2014 Date of Current Version: 27 January 2015 Issue Date: April 2015  DOI 10.1109/JSEN.2014.2371773

This paper is behind a paywall.