“Seeking” Artificial Photosynthesis

The excessive atmospheric carbon dioxide that is driving global climate change could be harnessed into a renewable energy technology that would be a win for both the environment and the economy. That is the lure of artificial photosynthesis in which the electrochemical reduction of carbon dioxide is used to produce clean, green and sustainable fuels.

However, finding a catalyst for reducing carbon dioxide that is highly selective and efficient has proven to be a huge scientific challenge. Meeting this challenge in the future should be easier thanks to new research results from Berkeley Lab. Peidong Yang, a chemist with Berkeley Lab’s Materials Sciences Division, led a study in which bimetallic nanoparticles of gold and copper were used as the catalyst for the carbon dioxide reduction. The results experimentally revealed for the first time the critical influence of the electronic and geometric effects in the reduction reaction (“Synergistic geometric and electronic effects for electrochemical reduction of carbon dioxide using gold-copper bimetallic nanoparticles”).

This TEM shows gold–copper bimetallic nanoparticles used as catalysts for the reduction of carbon dioxide, a key reaction for artificial photosynthesis. “Acting synergistically, the electronic and geometric effects dictate the binding strength for reaction intermediates and consequently the catalytic selectivity and efficiency in the electrochemical reduction of carbon dioxide,” Yang says. “In the future, the design of carbon dioxide reduction catalysts with good activity and selectivity will require the careful balancing of these two effects as revealed in our study.”

Yang, who also holds appointments with the University of California (UC) Berkeley and the Kavli Energy NanoSciences Institute at Berkeley, is a leading authority on nanoparticle phenomena. His most recent research has focused on nanocatalysts fashioned from metal alloys rather than a single metal such as gold, tin or copper. “By alloying, we believe we can tune the binding strength of intermediates on a catalyst surface to enhance the reaction kinetics for the carbon dioxide reduction,” he says.

“Nanoparticles provide an ideal platform for studying this effect because, through appropriate synthetic processes, we can access a wide range of compositions, sizes and shapes, allowing for a deeper understanding of catalyst performance through precise control of active sites.” In addition, Yang says, nanoparticle as catalysts have high surface-to-volume and surface-to-mass ratios that are advantageous for achieving high catalytic activity. For this new study, uniform gold–copper bimetallic nanoparticles with different compositions were assembled into ordered monolayers then observed during carbon dioxide reduction.

“The ordered monolayers served as a well-defined platform that enabled us to better understand their fundamental catalytic activity in carbon dioxide reduction,” Yang says. “Based on our observations, the activity of the gold-copper bimetallic nanoparticles can be explained in terms of the electronic effect, in which the binding of intermediates can be tuned using different surface compositions, and the geometric effect, in which the local atomic arrangement at the active site allows the catalyst to deviate from the scaling relation.” The effects Yang and his colleagues observed for gold-copper bimetallic nanoparticles should hold true for other carbon dioxide reduction catalysts as well. “We expect the effects we observed to be universal for a wide range of catalysts, as evidenced in other areas of catalysis such as the hydrogen evolution and oxygen reduction reactions,” says Dohyung Kim, a member of Yang’s research group and a collaborator in this study.

“The factors we have identified are based on the solid concept of electrocatalysis.” Knowing the influence of the electronic and geometric effects makes it possible to deduce how intermediate products in the reduction of carbon dioxide, such as carboxylic acid and carbon monoxide, will interact with the surface of a newly proposed catalyst and thereby provide the means for predicting the catalyst’s performance. Coupled with the exceptional structuring of active catalytic sites made possible by the use of nanoparticles, the path is paved, Yang and his colleagues believe, for unprecedented improvements in electrochemical carbon dioxide reduction.

“My group is now using the insights gained from this study in the design of next generation carbon dioxide reduction catalysts,” Yang says.

A paper describing this research has been published in Nature Communications entitled “Synergistic geometric and electronic effects for electrochemical reduction of carbon dioxide using gold–copper bimetallic nanoparticles.” Yang is the corresponding author and Kim is the lead author. The other co-authors are Joaquin Resasco, Yi Yu and Abdullah Mohamed Asiri.

Source: Lawrence Berkeley National Laboratory

A Plant-Based Battery with Neutrons, Simulation

When Orlando Rios first started analyzing samples of carbon fibers made from a woody plant polymer known as lignin, he noticed something unusual. The material’s microstructure—a mixture of perfectly spherical nanoscale crystallites distributed within a fibrous matrix—looked almost too good to be true.

“I thought, this looks like a material that people would go through a lot of work modifying graphite to make it look this way,” said Rios, a materials scientist at the U.S. Dept. of Energy (DOE)’s Oak Ridge National Laboratory (ORNL). “It had a really distinct microstructure from any other graphite I’d seen.”

Rios and his colleagues soon realized the lignin fiber’s unique structure could make it useful as a battery anode, potentially improving upon graphitic materials found in most lithium-ion batteries. Lignin, a low-cost byproduct of the pulp, paper and biofuels industries, could be transformed into a cheaper version of highly engineered graphite through a simple and industrially scalable manufacturing process.

Researchers at ORNL and the Univ. of Tennessee are studying the structure of plant-based battery materials by combining neutron experiments and supercomputer simulations. The molecular model pictured above shows the battery anode’s composition: amorphous carbon (blue), crystalline carbon (green) and hydrogen (white.)

“We start with the fibers when they’re in a polymer state and then fuse them together by essentially melting and burning them,” Rios said. “Then you have a structure that looks like a mat or piece of paper. You can take this material, place it in a battery and you’re done. It’s ready to go.”

Initial testing of the lignin-derived battery showed promising results in terms of capacity and cycling stability, but the researchers wanted to understand how and why the material behaved so differently from other graphites. Rios began collaborating with the Univ. of Tennessee’s Computational Materials Group, led by David Keffer, to further examine the fibers’ structure and behavior.

“There aren’t many techniques we can use to study these unique materials made of crystalline domains within an amorphous matrix,” said UT’s Nicholas McNutt, a graduate student in Keffer’s group. “We wanted to tie together some of Oak Ridge National Lab’s best resources—neutrons and computers—and see what we could do.”

The team ran neutron scattering experiments at ORNL’s Spallation Neutron Source (SNS) to analyze how lignin-based fiber samples reacted with lithium. The SNS is a DOE Office of Science user facility that provides the most intense pulsed neutron beams in the world for scientific research and industrial development.

Using the neutron data, the team developed computational models and ran simulations on supercomputers including the Oak Ridge Leadership Computing Facility’s (OLCF) Titan, supported by DOE’s Office of Science, and UT’s Kraken, supported by the National Science Foundation. The team detailed its approach in the Journal of Applied Crystallography.

“Our models allow us to take experimental neutron scattering data and predict things about the local atomic structure,” McNutt said. “We are using computation to understand experimental data in a way that you couldn’t do before.”

The initial combination of neutron experiments and simulation gave the UT-ORNL team a first glimpse into how the material’s structure affects its overall performance. Now that they have confirmed their model’s accuracy, the researchers plan on applying the technique to how the material’s structure changes with and without added lithium, mimicking the charging and discharging cycles of a real battery.

“The most useful aspect of simulation is that we can see exactly what the lithium is doing in these structures,” McNutt said. “If we can see where it’s stored, how much of it is stored, what area of the structure it diffuses through, we can basically figure out all the reasons that make these low-cost materials high-performance. Once we know that, we can help guide the manufacturing process.”

Source: Oak Ridge National Laboratory

Nanoparticles Stagger Delivery of Two Drugs: Knock Out Aggressive Cancer Tumors

 

Chemotherapy timing is key to success: Nanoparticles that stagger delivery of two drugs knock out aggressive tumors in mice.

Cambridge, MA | Posted on May 8th, 2014

 

Abstract:

MIT researchers have devised a novel cancer treatment that destroys tumor cells by first disarming their defenses, then hitting them with a lethal dose of DNA damage.

In studies with mice, the research team showed that this one-two punch, which relies on a nanoparticle that carries two drugs and releases them at different times, dramatically shrinks lung and breast tumors. The MIT team, led by Michael Yaffe, the David H. Koch Professor in Science, and Paula Hammond, the David H. Koch Professor in Engineering, describe the findings in the May 8 online edition of Science Signaling.

“I think it’s a harbinger of what nanomedicine can do for us in the future,” says Hammond, who is a member of MIT’s Koch Institute for Integrative Cancer Research. “We’re moving from the simplest model of the nanoparticle — just getting the drug in there and targeting it — to having smart nanoparticles that deliver drug combinations in the way that you need to really attack the tumor.”

Doctors routinely give cancer patients two or more different chemotherapy drugs in hopes that a multipronged attack will be more successful than a single drug. While many studies have identified drugs that work well together, a 2012 paper from Yaffe’s lab was the first to show that the timing of drug administration can dramatically influence the outcome.

In that study, Yaffe and former MIT postdoc Michael Lee found they could weaken cancer cells by administering the drug erlotinib, which shuts down one of the pathways that promote uncontrolled tumor growth. These pretreated tumor cells were much more susceptible to treatment with a DNA-damaging drug called doxorubicin than cells given the two drugs simultaneously.

“It’s like rewiring a circuit,” says Yaffe, who is also a member of the Koch Institute. “When you give the first drug, the wires’ connections get switched around so that the second drug works in a much more effective way.”

Erlotinib, which targets a protein called the epidermal growth factor (EGF) receptor, found on tumor cell surfaces, has been approved by the Food and Drug Administration to treat pancreatic cancer and some types of lung cancer. Doxorubicin is used to treat many cancers, including leukemia, lymphoma, and bladder, breast, lung, and ovarian tumors.

Staggering these drugs proved particularly powerful against a type of breast cancer cell known as triple-negative, which doesn’t have overactive estrogen, progesterone, or HER2 receptors. Triple-negative tumors, which account for about 16 percent of breast cancer cases, are much more aggressive than other types and tend to strike younger women.

That was an exciting finding, Yaffe says. “The problem was,” he adds, “how do you translate that into something you can actually give a cancer patient?”

From lab result to drug delivery

To approach this problem, Yaffe teamed up with Hammond, a chemical engineer who has previously designed several types of nanoparticles that can carry two drugs at once. For this project, Hammond and her graduate student, Stephen Morton, devised dozens of candidate particles. The most effective were a type of particle called liposomes — spherical droplets surrounded by a fatty outer shell.

The MIT team designed their liposomes to carry doxorubicin inside the particle’s core, with erlotinib embedded in the outer layer. The particles are coated with a polymer called PEG, which protects them from being broken down in the body or filtered out by the liver and kidneys. Another tag, folate, helps direct the particles to tumor cells, which express high quantities of folate receptors.

Once the particles reach a tumor and are taken up by cells, the particles start to break down. Erlotinib, carried in the outer shell, is released first, but doxorubicin release is delayed and takes more time to seep into cells, giving erlotinib time to weaken the cells’ defenses. “There’s a lag of somewhere between four and 24 hours between when erlotinib peaks in its effectiveness and the doxorubicin peaks in its effectiveness,” Yaffe says.

The researchers tested the particles in mice implanted with two types of human tumors: triple-negative breast tumors and non-small-cell lung tumors. Both types shrank significantly. Furthermore, packaging the two drugs in liposome nanoparticles made them much more effective than the traditional forms of the drugs, even when those drugs were given in a time-staggered order.

As a next step before possible clinical trials in human patients, the researchers are now testing the particles in mice that are genetically programmed to develop tumors on their own, instead of having human tumor cells implanted in them.

The researchers believe that time-staggered delivery could also improve other types of chemotherapy. They have devised several combinations involving cisplatin, a commonly used DNA-damaging drug, and are working on other combinations to treat prostate, head and neck, and ovarian cancers. At the same time, Hammond’s lab is working on more complex nanoparticles that would allow for more precise loading of the drugs and fine-tuning of their staggered release.

“With a nanoparticle delivery platform that allows us to control the relative rates of release and the relative amounts of loading, we can put these systems together in a smart way that allows them to be as effective as possible,” Hammond says.

Morton and Lee are the lead authors of the Science Signaling paper. Postdocs Zhou Deng, Erik Dreaden, and Kevin Shopsowitz, visiting student Elise Siouve, and graduate student Nisarg Shah also contributed to the research. The work was funded by the National Institutes of Health, the Center for Cancer Nanotechnology Excellence, and a Breast Cancer Alliance Exceptional Project Grant.

Written by Anne Trafton, MIT News Office

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Copyright © Massachusetts Institute of Technology

Nanoparticles can activate immune cells, treat diseases

Washington, Feb 24 (IANS) Scientists have developed a new system that can precisely deliver anti-inflammatory drugs to immune cells gone out of control, while sparing their well-behaved counterparts.

 

The findings by researchers at the University of Illinois at Chicago were published online Feb 23 in Nature Nanotechnology.

The system uses nanoparticles made of tiny bits of protein designed to bind to unique receptors found only on neutrophils, a type of immune cell engaged in detrimental acute and chronic inflammatory responses.

In a normal immune response, neutrophils circulating in the blood respond to signals given off by injured or damaged blood vessels and begin to accumulate at the injury, where they engulf bacteria or debris from injured tissue that might cause infection.

In chronic inflammation, neutrophils can pile up at the site of injury, sticking to the blood vessel walls and to each other and contributing to tissue damage, reported Science Daily.

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

Malik is also lead author of the paper.

“The nanoparticle is very much like a Trojan horse,” Malik said. “It binds to a receptor found only on these activated, sticky neutrophils, and the cell automatically engulfs whatever binds there. Because circulating neutrophils lack these receptors, the system is incredibly precise and targets only those immune cells that are actively contributing to inflammatory disease.”

Malik said, the findings “show that nanoparticles can be used to deliver drugs in a highly targeted, specific fashion to activated immune cells and could be designed to treat a broad range of inflammatory diseases”.

New Technique Targets Specific Areas of Cancer Cells with Different Drugs

Release Date: 01.06.14 Filed under

Releases

Researchers have developed a technique for creating nanoparticles that carry two different cancer-killing drugs into the body and deliver those drugs to separate parts of the cancer cell where they will be most effective. The technique was developed by researchers at North Carolina State University and the University of North Carolina at Chapel Hill.

“In testing on laboratory mice, our technique resulted in significant improvement in breast cancer tumor reduction as compared to conventional treatment techniques,” says Dr. Zhen Gu, senior author of a paper on the research and an assistant professor in the joint biomedical engineering program at NC State and UNC-Chapel Hill.

 

“Cancer cells can develop resistance to chemotherapy drugs, but are less likely to develop resistance when multiple drugs are delivered simultaneously,” Gu says. “However, different drugs target different parts of the cancer cell. For example, the protein drug TRAIL is most effective against the cell membrane, while doxorubicin (Dox) is most effective when delivered to the nucleus. We’ve come up with a sequential and site-specific delivery technique that first delivers TRAIL to cancer cell membranes and then penetrates the membrane to deliver Dox to the nucleus.”

Gu’s research team developed nanoparticles with an outer shell made of hyaluronic acid (HA) woven together with TRAIL. The HA interacts with receptors on cancer cell membranes, which “grab” the nanoparticle. Enzymes in the cancer cell environment break down the HA, releasing TRAIL onto the cell membrane and ultimately triggering cell death.

When the HA shell breaks down, it also reveals the core of the nanoparticle, which is made of Dox that is embedded with peptides that allow the core to penetrate into the cancer cell. The cancer cell encases the core in a protective bubble called an endosome, but the peptides on the core cause the endosome to begin breaking apart. This spills the Dox into the cell where it can penetrate the nucleus and trigger cell death.

“We designed this drug delivery vehicle using a ‘programmed’ strategy,” says Tianyue Jiang, a lead author in Dr. Gu’s lab. “Different drugs can be released at the right time in their right places,” adds Dr. Ran Mo, a postdoctoral researcher in Gu’s lab and the other lead author.

“This research is our first proof of concept, and we will continue to optimize the technique to make it even more efficient,” Gu says. “The early results are very promising, and we think this could be scaled up for large-scale manufacturing.”

The paper, “Gel–Liposome-Mediated Co-Delivery of Anticancer Membrane-Associated Proteins and Small-Molecule Drugs for Enhanced Therapeutic Efficacy,” is published online in Advanced Functional Materials. Co-authors of the paper are Adriano Bellotti, an undergraduate at NC State, and Dr. Jianping Zhou, a professor at China Pharmaceutical University.

-shipman-

Note to Editors: The study abstract follows.

“Gel–Liposome-Mediated Co-Delivery of Anticancer Membrane-Associated Proteins and Small-Molecule Drugs for Enhanced Therapeutic Efficacy”

Authors: Tianyue Jiang, Ran Mo, and Zhen Gu, North Carolina State University and University of North Carolina at Chapel Hill; Adriano Bellotti, North Carolina State University; Jianping Zhou, China Pharmaceutical University.

Published: online Jan. 2, 2014, Advanced Functional Materials

Abstract: A programmed drug-delivery system that can transport different anticancer therapeutics to their distinct targets holds vast promise for cancer treatment. Herein, a core–shell-based “nanodepot” consisting of a liposomal core and a crosslinked-gel shell (designated Gelipo) is developed for the sequential and site-specific delivery (SSSD) of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and doxorubicin (Dox). As a small-molecule drug intercalating the nuclear DNA, Dox is loaded in the aqueous core of the liposome, while TRAIL, acting on the death receptor (DR) on the plasma membrane, is encapsulated in the outer shell made of crosslinked hyaluronic acid (HA). The degradation of the HA shell by HAase that is concentrated in the tumor environment results in the rapid extracellular release of TRAIL and subsequent internalization of the liposomes. The parallel activity of TRAIL and Dox show synergistic anticancer efficacy. The half-maximal inhibitory concentration (IC50) of TRAIL and Dox co-loaded Gelipo (TRAIL/Dox-Gelipo) toward human breast cancer (MDA-MB-231) cells is 83 ng mL^–1 (Dox concentration), which presents a 5.9-fold increase in the cytotoxicity compared to 569 ng mL^–1 of Dox-loaded Gelipo (Dox-Gelipo). Moreover, with the programmed choreography, Gelipo significantly improves the inhibition of the tumor growth in the MDA-MB-231 xenograft tumor animal model.

How nanotechnology can advance regenerative medicine

(Nanowerk News) Nanotechnology may provide new  strategies for regenerative medicine, including better tools to improve or  restore damaged tissues, according to a review paper by Taiwanese researchers.

Published in the journal Science and Technology of Advanced  Materials, the paper (“Nanotechnology in the regulation of stem cell  behavior”) summarizes the current state of knowledge on nanotechnology with  application to stem cell biology.

Stem cells are considered an important potential source for  repairing damaged human tissues. Researchers have found that the adhesion,  growth, and differentiation of stem cells are likely controlled by their  surrounding microenvironment, which contains both chemical and physical cues.  These cues include the “nanotopography” of the complex extracellular matrix or  architecture that forms a network for human tissues.

In their review paper, Yang-Kao Wang and colleagues describe  studies showing how this nanotopography (which includes nanosized pores,  grooves, ridges, etc.) plays important roles in the behaviour and fate of stem  cells. The authors also discuss the application of nanoparticles to stem cell  isolation, tracking and imaging; how to translate nanotechnology from two to  three dimensions; and the potential limitations of using nanomaterials in stem  cell biology.

The paper concludes that “understanding [the] interactions of  nanomaterials with stem cells may provide knowledge applicable to [the  development of improved] cell-scaffold combinations in tissue engineering and  regenerative medicine.”

Source: imec

Read more: http://www.nanowerk.com/news2/newsid=33034.php#ixzz2jX1zjALD

(Solar) Cell a Million?

SOLAR cells were once a bespoke product, reserved for satellites and military use. In 1977 a watt of solar generating capacity cost $77. That has now come down to about 80 cents, and solar power is beginning to compete with the more expensive sort of conventionally generated electricity. If the price came down further, though, solar might really hit the big time—and that is the hope of Henry Snaith, of Oxford University, and his colleagues. As he described recently in Science, Dr Snaith plans to replace silicon, the material used to make most solar cells, with a substance called a perovskite. This, he believes, could cut the cost of a watt of solar generating capacity by three-quarters.

When light falls on a solar cell, it knocks electrons away from the cell’s material and leaves behind empty spaces called holes. Electrons and holes then flow in opposite directions and the result is an electric current.

 

The more electrons and holes there are, and the faster they flow, the bigger the current will be. Electrons, however, often get captured by holes while still inside the cell, and cannot therefore contribute to the current. The average distance an electron travels in a material before it gets captured is known as that material’s diffusion length. The larger the diffusion length, the more efficient the cell.

The silicon used in commercial solar cells has a diffusion length of ten nanometres (billionth of a metre), which is not much. Partly for this reason a silicon cell’s efficiency at converting incident light into electricity is less than 10%. Dr Snaith’s perovskite does better. It has a diffusion length of 1,000 nanometres, giving it an efficiency of 15%. And this, Dr Snaith says, has been achieved without much tweaking of the material. The implication is that it could be made more efficient still.

Perovskites are substances composed of what are known as cubo-octahedral crystals—in other words, cubes with the corners cut off. They thus have six octagonal faces and eight triangular ones. Perovskite itself is a natually occuring mineral, calcium titanium oxide, but lots of other elemental combinations adopt the same shape, and tinkering with the mix changes the frequency of the light the crystal absorbs best.

Dr Snaith’s perovskite is a particularly sophisticated one. It has an organic part, made of carbon, hydrogen and nitrogen, and an inorganic part, made of lead, iodine and chlorine. The organic part acts as a dye, absorbing lots of sunlight. The inorganic part helps conduct the electrons thus released.

It is also cheap to make. Purifying silicon requires high (and therefore costly) temperatures. Dr Snaith’s perovskite can be blended at room temperature. Laboratory versions of cells made from it cost about 40 cents per watt (ie, about half the cost of commercial silicon-based solar cells). At an industrial scale, Dr Snaith expects, that will halve again.

There are caveats, of course. The new perovskite is such a recent invention that its durability has not been properly tested. Many otherwise-promising materials fail to survive constant exposure to the sun, a sine qua non of being a solar cell. And the process of converting a laboratory-made cell into a mass-manufactured one is not always straight forward.

If it leaps these hurdles, though, Dr Snaith’s material will be a strong challenger for silicon. As solar power-generation becomes a mainstream technology over the next few years, the once-strange word “perovskite” may enter everyday language.

Physicists decode decision circuit of cancer metastasis

Rice U. research reveals three-way genetic switch for cancer metastasis

 

HOUSTON — (Oct. 24, 2013) — Cancer researchers from Rice University have deciphered the operating principles of a genetic switch that cancer cells use to decide when to metastasize and invade other parts of the body. The study found that the on-off switch’s dynamics also allows a third choice that lies somewhere between “on” and “off.” The extra setting both explains previously confusing experimental results and opens the door to new avenues of cancer treatment.

The study appears online this week in the Early Edition of the Proceedings of the National Academy of Sciences.

Eshel Ben-Jacob

“Cancer cells behave in complex ways, and this work shows how such complexity can arise from the operation of a relatively simple decision-making circuit,” said study co-author Eshel Ben-Jacob, a senior investigator at Rice’s Center for Theoretical Biological Physics (CTBP) and adjunct professor of biochemistry and cell biology at Rice. “By stripping away the complexity and starting with first principles, we get a glimpse of the ‘logic of cancer’ — the driver of the disease’s decision to spread.”

In the PNAS study, Ben-Jacob and CTBP colleagues José Onuchic, Herbert Levine, Mingyang Lu and Mohit Kumar Jolly describe a new theoretical framework that allowed them to model the behavior of microRNAs in decision-making circuits. To test the framework, they modeled the behavior of a decision-making genetic circuit that cells use to regulate the forward and backward transitions between two different cell states, the epithelial and mesenchymal. Known respectively as the E-M transition (EMT) and the M-E transition (MET), these changes in cell state are vital for embryonic development, tissue engineering and wound healing. During the EMT, some cells also form a third state, a hybrid that is endowed with a special mix of both epithelial and mesenchymal abilities, including group migration.

The EMT transition is also a hallmark of cancer metastasis. Cancer cells co-opt the process to allow tumor cells to break away, migrate to other parts of the body and establish a new tumor. To find ways to shut down metastasis, cancer researchers have conducted dozens of studies about the genetic circuitry that activates the EMT.

One clear finding from previous studies is that a two-component genetic switch is the key to both the EMT and MET. The switch contains two specialized pairs of proteins. One pair is SNAIL and microRNA34 (SNAIL/miR34), and the other is ZEB and microRNA200 (ZEB/miR200).

Each pair is “mutually inhibitory,” meaning that the presence of one of the partners inhibits the production of the other.

This is an artist’s depiction of the dangers of metastasis, the process by which cancer cells migrate and establish tumors throughout the body. A new study from Rice University cancer researchers details the workings of key genetic circuits involved in metastasis. Credit: photos.com/Rice University

In the mesenchymal cell state — the state that corresponds to cancer metastasis — both SNAIL and ZEB must be present in high levels. In the epithelial state, the microRNA partners dominate, and neither ZEB nor SNAIL is available in high levels.

“Usually, if you have two genes that are mutually limiting, you have only two possibilities,”

Ben-Jacob said. “In the first case, gene A is highly expressed and inhibits gene B. In the other, gene B is highly expressed and it inhibits A. This is true in the case of ZEB and miR200. One of these is ‘on’ and the other is ‘off,’ so it’s clear that this is the decision element in the switch.”

SNAIL and miR34 interact more weakly. As a result, both can be present at the same time, with the amount of each varying based upon inputs from a number of other proteins, including several other cancer genes.

“One of the most important things the model showed us was how SNAIL and miR34 act as an integrator,” Ben-Jacob said. “This part of the circuit is acted on by multiple cues, and it integrates those signals and feeds information into the decision element. It does this based upon the level of SNAIL, which activates ZEB and inhibits miR200.”

In modeling the ZEB/miR200 decision circuit, the team found that it operates as a “ternary” or three-way, switch. The reason for this is that ZEB has the ability to activate itself by a positive feedback loop, which allows the cell to keep intermediate levels of all four proteins in the switch under some conditions.

Ben-Jacob said the hybrid, or partially on-off state, also supports cancer metastasis by enabling collective cell migration and by imparting stem-cell properties that help migrating cancer cells evade the immune system and anticancer therapies.

“Now that we understand what drives the cell to select between the various states, we can begin to think of new ways to outsmart cancer,” Ben-Jacob said. “We can think about coaxing the cancer to make the decision that we want, to convert itself into a state that we are ready to attack with a particularly effective treatment.”

José Onuchic

The cancer-metastasis results correspond with findings from previous studies by Ben-Jacob and Onuchic into the collective decision-making processes of bacteria and into new strategies to combat cancer by timing the delivery of multiple drugs to interrupt the decision-making processes of cancer.

“At CTBP, we allow the underlying physics of a system to guide our examination of its biological properties,” said Onuchic, CTBP co-director and Rice’s Harry C. and Olga K. Wiess Professor of Physics and Astronomy and professor of chemistry and of biochemistry and cell biology. “In this case, that approach led us to develop a powerful model for simulating the decision-making circuitry involved in cancer metastasis. Going forward, we plan to see how this circuit interacts with others to produce a variety of cancer cells, including cancer stem cells.”

The research is supported by the National Science Foundation, the Cancer Prevention and Research Institute of Texas and the Tauber Family Funds at Tel Aviv University. Lu is a postdoctoral researcher at CTBP, and Jolly is a graduate student in bioengineering. Levine is co-director of CTBP and Rice’s Karl F. Hasselmann Professor in Bioengineering. Ben-Jacob is also the Maguy-Glass Professor in Physics of Complex Systems and professor of physics and astronomy at Tel Aviv University.

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A high-resolution IMAGE is available for download at: http://news.rice.edu/wp-content/uploads/2013/10/1021-FATE-abstract-lg.jpg CAPTION: This is an artist’s depiction of the dangers of metastasis, the process by which cancer cells migrate and establish tumors throughout the body. A new study from Rice University cancer researchers details the workings of key genetic circuits involved in metastasis. CREDIT: photos.com/Rice University

A copy of the PNAS paper is available at:

http://www.pnas.org/content/early/2013/10/23/1318192110.abstract

Nanotech system, cellular heating may improve treatment of ovarian cancer

Oct 17, 2013 

    

       Enlarge        

 A new drug delivery system that incorporates heat, nanotechnology and chemotherapy shows promise in improving the treatment of ovarian cancer. Credit: Oregon State University

The combination of heat, chemotherapeutic drugs and an innovative delivery system based on nanotechnology may significantly improve the treatment of ovarian cancer while reducing side effects from toxic drugs, researchers at Oregon State University report in a n

The findings, so far done only in a laboratory setting, show that this one-two punch of mild hyperthermia and chemotherapy can kill 95 percent of ovarian cancer cells, and scientists say they expect to improve on those results in continued research.

The work is important, they say, because ovarian cancer – one of the leading causes of cancer-related deaths in women – often develops resistance to chemotherapeutic drugs if it returns after an initial remission. It kills more than 150,000 women around the world every year.

“Ovarian cancer is rarely detected early, and because of that chemotherapy is often needed in addition to surgery,” said Oleh Taratula, an assistant professor in the OSU College of Pharmacy. “It’s essential for the chemotherapy to be as effective as possible the first time it’s used, and we believe this new approach should help with that.”

It’s known that elevated temperatures can help kill cancer cells, but heating just the cancer cells is problematic. The new system incorporates the use of iron oxide nanoparticles that can be coated with a cancer-killing drug and then heated once they are imbedded in the cancer cell.

Other features have also been developed to optimize the new system, in an unusual collaboration between engineers, material science experts and pharmaceutical researchers.

A peptide is used that helps guide the nanoparticle specifically to cancer cells, and the nanoparticle is just the right size – neither too big nor too small – so the immune system will not reject it. A special polyethylene glycol coating further adds to the “stealth” effect of the nanoparticles and keeps them from clumping up. And the interaction between the cancer drug and a polymer on the nanoparticles gets weaker in the acidic environment of cancer cells, aiding release of the drug at the right place.

“The hyperthermia, or heating of cells, is done by subjecting the magnetic nanoparticles to an oscillating, or alternating magnetic field,” said Pallavi Dhagat, an associate professor in the OSU School of Electrical Engineering and Computer Science, and co-author on the study. “The nanoparticles absorb energy from the oscillating field and heat up.”

The result, in laboratory tests with ovarian cancer cells, was that a modest dose of the chemotherapeutic drug, combined with heating the cells to about 104 degrees, killed almost all the cells and was far more effective than either the drug or heat treatment would have been by itself.

Doxorubicin, the cancer drug, by itself at the level used in these experiments would leave about 70 percent of the cancer cells alive. With the new approach, only 5 percent were still viable.

The work was published in the International Journal of Pharmaceutics, as a collaboration of researchers in the OSU College of Pharmacy, College of Engineering, and Ocean NanoTech of Springdale, Ark. It was supported by the Medical Research Foundation of Oregon, the PhRMA Foundation and the OSU College of Pharmacy.

“I’m very excited about this delivery system,” Taratula said. “Cancer is always difficult to treat, and this should allow us to use lower levels of the toxic chemotherapeutic drugs, minimize side effects and the development of drug resistance, and still improve the efficacy of the treatment. We’re not trying to kill the cell with heat, but using it to improve the function of the drug.”

Iron oxide particles had been used before in some medical treatments, researchers said, but not with the complete system developed at OSU. Animal tests, and ultimately human trials, will be necessary before the new system is available for use.

Drug delivery systems such as this may later be applied to other forms of cancer, such as prostate or pancreatic cancer, to help improve the efficacy of chemotherapy in those conditions, Taratula said.

Explore further:     New ovarian cancer treatment succeeds in the lab

Read more at: http://phys.org/news/2013-10-nanotech-cellular-treatment-ovarian-cancer.html#jCp

Read more at: http://phys.org/news/2013-10-nanotech-cellular-treatment-ovarian-cancer.html#jCp

Nanosensors Could Aid Drug Manufacturing

 CAMBRIDGE, Mass. MIT News Office: Chemical engineers find that arrays of carbon nanotubes can detect flaws in drugs and help improve production.      — MIT chemical engineers have discovered that arrays of billions of nanoscale sensors have unique properties that could help pharmaceutical companies produce drugs — especially those based on antibodies — more safely and efficiently.
Using these sensors, the researchers were able to characterize variations in the binding strength of antibody drugs, which hold promise for treating cancer and other diseases. They also used the sensors to monitor the structure of antibody molecules, including whether they contain a chain of sugars that interferes with proper function.
“This could help pharmaceutical companies figure out why certain drug formulations work better than others, and may help improve their effectiveness,” says Michael Strano, an MIT professor of chemical engineering and senior author of a recent paper describing the sensors in the journal ACS Nano.
The team also demonstrated how nanosensor arrays could be used to determine which cells in a population of genetically engineered, drug-producing cells are the most productive or desirable, Strano says. Lead author of the paper is Nigel Reuel, a graduate student in Strano’s lab. The labs of MIT faculty members Krystyn Van Vliet, Christopher Love and Dane Wittrup also contributed, along with scientists from Novartis.
Testing drug strength
Strano and other scientists have previously shown that tiny, nanometer-sized sensors, such as carbon nanotubes, offer a powerful way to detect minute quantities of a substance. Carbon nanotubes are 50,000 times thinner than a human hair, and they can bind to proteins that recognize a specific target molecule. When the target is present, it alters the fluorescent signal produced by the nanotube in a way that scientists can detect.
Some researchers are trying to exploit large arrays of nanosensors, such as carbon nanotubes or semiconducting nanowires, each customized for a different target molecule, to detect many different targets at once. In the new study, Strano and his colleagues wanted to explore unique properties that emerge from large arrays of sensors that all detect the same thing.
The first feature they discovered, through mathematical modeling and experimentation, is that uniform arrays can measure the distribution in binding strength of complex proteins such as antibodies. Antibodies are naturally occurring molecules that play a key role in the body’s ability to recognize and defend against foreign invaders. In recent years, scientists have been developing antibodies to treat disease, particularly cancer. When those antibodies bind to proteins found on cancer cells, they stimulate the body’s own immune system to attack the tumor.
For antibody drugs to be effective, they must strongly bind their target. However, the manufacturing process, which relies on nonhuman, engineered cells, does not always generate consistent, uniformly binding batches of antibodies.

Currently, drug companies use time-consuming and expensive analytical processes to test each batch and make sure it meets the regulatory standards for effectiveness. However, the new MIT sensor could make this process much faster, allowing researchers to not only better monitor and control production, but also to fine-tune the manufacturing process to generate a more consistent product.
“You could use the technology to reject batches, but ideally you’d want to use it in your upstream process development to better define culture conditions, so then you wouldn’t produce spurious lots,” Reuel says.
Measuring weak interactions
Another useful trait of such sensors is their ability to measure very weak binding interactions, which could also help with antibody drug manufacturing.
Antibodies are usually coated with long sugar chains through a process called glycosylation. These sugar chains are necessary for the drugs to be effective, but they are extremely hard to detect because they interact so weakly with other molecules. Drug-manufacturing organisms that synthesize antibodies are also programmed to add sugar chains, but the process is difficult to control and is strongly influenced by the cells’ environmental conditions, including temperature and acidity.
Without the appropriate glycosylation, antibodies delivered to a patient may elicit an unwanted immune response or be destroyed by the body’s cells, making them useless.
“This has been a problem for pharmaceutical companies and researchers alike, trying to measure glycosylated proteins by recognizing the carbohydrate chain,” Strano says. “What a nanosensor array can do is greatly expand the number of opportunities to detect rare binding events. You can measure what you would otherwise not be able to quantify with a single, larger sensor with the same sensitivity.” This tool could help researchers determine the optimal conditions for the correct degree of glycosylation to occur, making it easier to consistently produce effective drugs.
Mapping production
The third property the researchers discovered is the ability to map the production of a molecule of interest. “One of the things you would like to do is find strains of particular organisms that produce the therapeutic that you want,” Strano says. “There are lots of ways of doing this, but none of them are easy.”
The MIT team found that by growing the cells on a surface coated with an array of nanometer-sized sensors, they could detect the location of the most productive cells. In this study, they looked for an antibody produced by engineered human embryonic kidney cells, but the system could also be tailored to other proteins and organisms.
Once the most productive cells are identified, scientists look for genes that distinguish those cells from the less productive ones and engineer a new strain that is highly productive, Strano says.
The researchers have built a briefcase-sized prototype of their sensor that they plan to test with Novartis, which funded the research along with the National Science Foundation.
“Carbon nanotubes coupled to protein-binding entities are interesting for several areas of bio-manufacturing as they offer great potential for online monitoring of product levels and quality. Our collaboration has shown that carbon nanotube-based fluorescent sensors are applicable for such purposes, and I am eager to follow the maturation of this technology,” says Ramon Wahl, an author of the paper and a principal scientist at Novartis.