Fine-tuning Nanotech to Target Cancer

Programmable nanoparticles have shown promise in early cancer trials, and may finally fulfill the promise of nanomedicine.

• BY SUSAN YOUNG

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The results of the human trials are startling. Even at a lower-than-usual dose, multiple lung metastases shrank or even disappeared after one patient received only two-hour-long intravenous infusions of an experimental cancer drug. Another patient saw her cervical tumor reduce by nearly 60 percent after six months of treatment. Though the drug trial—by Bind Biosciences in Cambridge, Massachusetts—of an experimental nanotechnology-based technique was designed simply to show whether the technology is safe, the encouraging results revive hopes that nanomedicine could realize its elusive promise.

For more than a decade, researchers have been trying to develop nanoparticles that would deliver drugs more effectively and safely. The idea is that a nanoparticle containing a drug compound could selectively target tumor cells or otherwise diseased cells, and avoid healthy ones. Antibodies or other molecules can be attached to the nanoparticle and used to precisely identify target cells. "One of the largest advantages of nanotechnology is you can engineer things in particle form so that chemotherapeutics can be targeted to tumor cells, protecting the healthy cells of the body and protecting patients from side effects," says Sara Hook, nanotechnology development projects manager with the National Cancer Institute.

But executing this vision has been difficult. One challenge: a drug's behavior in the body can change dramatically when it's combined with nanoparticles. A nanoparticle can change a drug's solubility, toxicity, speed of action, and more—sometimes beneficially, sometimes not. If a drug's main problem is that it's toxic to off-target organs, then nanotechnology can ensure that it's delivered to diseased cells instead of healthy cells. But if a drug depends on being absorbed quickly by diseased cells to be effective, a nanoparticle may slow the process and turn an optimal therapeutic into second best.

Bind, which was launched in 2007, has attempted to overcome this problem by building its drug-targeting nanoparticles in a way that allows the company to systematically vary their structures and composition. Typically, targeted drug nanoparticles are produced in two steps: first, a drug is encapsulated in a nanoparticle, and second, the external surface of the particle is bound with targeting molecules that will steer the therapeutic ferry to diseased cells. Generating such nanoparticles can be difficult to control and replicate, which limits a researcher's ability to fine-tune the nanoparticle's surface properties. To avoid this pitfall, Bind synthesizes its drug-carrying nanoparticles using self-assembly.

Under the right conditions, the subunits of its nanoparticles—some of which already contain targeting molecules—assemble on their own. No complex and variable chemical reactions are needed to produce the nanoparticles, and the properties of each subunit can be tweaked. This also allows the company's researchers to test a variety of nanoparticle-drug combinations and identify the best candidates for a particular task. "We make hundreds of combinations to evaluate in order optimize the performance of each drug," says Jeff Hrkach, senior vice president of technology research and development.

Bind cofounder Omid Farokhzad, associate professor at Brigham Women's Hospital and Harvard Medical School, came up with the novel method for building nanoparticles while he was a postdoctoral researcher in the lab of Robert Langer, an MIT chemical engineering professor. Langer's group had already developed nanoparticles capable of releasing drugs in a controlled manner, but the particles did not yet seek out cancer cells specifically. Farokhzad's first challenge was to create nanoparticles whose molecular instructions would bring them to cancer cells, but which remained anonymous within the bloodstream so that the immune system wouldn't destroy them. The second was coming up with a robust and reproducible manufacturing process.

Instead, Farokhzad and Langer devised a method by which the building blocks of the nanoparticle and the drug self-assemble into a final product. Two types of polymer combine to form the tangled mesh of Bind's drug-laden spherical nanoparticle. One of these polymers has two chemically and structurally distinct regions, or "blocks": a water-insoluble block that forms part of the mesh that encapsulates the drug, and a water-soluble block that gives the final product a stealthy corona to evade the immune system. The other type of polymer has three blocks: the same two as the first, as well as a third region that contains a targeting molecule—the signal that will ensure the final particles attach to the desired cell types. The drug-carrying nanoparticles are formed by simply mixing these polymers together with the drug in the appropriate conditions.

The self-assembling polymers can be produced in a repeatable and scalable fashion. But the method has an additional benefit, one that may be the real key to Bind's success. The method by which the nanoparticles are built—from individual preparations of the two-block and three-block polymers—would also let researchers use high-throughput screening approaches, akin to how medicinal chemists design and test new drug compounds. Each block could be tweaked—extend one block, change the charge on another—and the relative amounts of each polymer could be varied. With so many parameters for tinkering, Bind's scientists can screen many combinations.

Its first drug in clinical trials, Bind-014, carries a widely used chemotherapeutic called docetaxel through the bloodstream to cancer cells. The drug is packaged inside a ball-like nanostructure made of biodegradable polymers that protect the drug and shield it from the body's immune system. The external surface of each nanoparticle is dotted with molecules that target cancerous cells. Once the nanoparticle has reached its target, it sticks to the outside of the cell, which triggers the cell to engulf the particle. The drug diffuses out of the particle at a controlled rate and is released into the deranged cell.

Mark Davis, a professor of chemical engineering at Caltech, is hopeful that the few ongoing trials of targeted nanoparticle therapeutics, which include one developed in his lab as well as Bind-014, will demonstrate the technology's potential. "The medical community isn't going to get excited until there is [an advanced human trial] where we can show what these targeted nanoparticles actually do for patients in a statistically significant way." For now, the results from the 17 patients enrolled in the phase I trial of Bind-014 look promising, but a real test of efficacy will have to wait until phase II trials, which are likely to start later this year.

The "programmable" design used by Bind may be key to bringing more nanoparticle-targeted drugs to trial. The company's methods could be applied to any existing drugs or compounds, including those that may have been shelved by pharmaceutical companies because they proved too toxic to the whole body. "We believe we can have a very broad platform of drugs that we can develop," says Hrkach.

Nanoparticles Home in On Brain Tumors, Boost Accuracy of Surgical Removal

Human brain scans. Like special-forces troops laser-tagging targets for a bomber pilot, tiny particles that can be imaged three different ways at once have enabled Stanford University School of Medicine scientists to remove brain tumors from mice with unprecedented accuracy. (Credit: © svedoliver / Fotolia)                                                                             Science Daily — Like special-forces troops laser-tagging targets for a bomber pilot, tiny particles that can be imaged three different ways at once have enabled Stanford University School of Medicine scientists to remove brain tumors from mice with unprecedented accuracy.

About 14,000 people are diagnosed annually with brain cancer in the United States. Of those cases, about 3,000 are glioblastomas, the most aggressive form of brain tumor. The prognosis for glioblastoma is bleak: the median survival time without treatment is three months. Surgical removal of such tumors -- a virtual imperative whenever possible -- prolongs the typical patient's survival by less than a year. One big reason for this is that it is almost impossible for even the most skilled neurosurgeon to remove the entire tumor while sparing normal brain.In a study published online April 15 in Nature Medicine, a team led by Sam Gambhir, MD, PhD, professor and chair of radiology, showed that the minuscule nanoparticles engineered in his lab homed in on and highlighted brain tumors, precisely delineating their boundaries and greatly easing their complete removal. The new technique could someday help improve the prognosis of patients with deadly brain cancers.

"With brain tumors, surgeons don't have the luxury of removing large amounts of surrounding normal brain tissue to be sure no cancer cells are left," said Gambhir, who is the Virginia and D.K. Ludwig Professor for Clinical Investigation in Cancer Research and director of the Molecular Imaging Program at Stanford. "You clearly have to leave as much of the healthy brain intact as you possibly can."

This is a real problem for glioblastomas, which are particularly rough-edged tumors. In these tumors, tiny fingerlike projections commonly infiltrate healthy tissues, following the paths of blood vessels and nerve tracts. An additional challenge is posed by micrometastases: minuscule tumor patches caused by the migration and replication of cells from the primary tumor. Micrometastases dotting otherwise healthy nearby tissue but invisible to the surgeon's naked eye can burgeon into new tumors.

Although brain surgery today tends to be guided by the surgeon's naked eye, new molecular imaging methods could change that, and this study demonstrates the potential of using high-technology nanoparticles to highlight tumor tissue before and during brain surgery.

The nanoparticles used in the study are essentially tiny gold balls coated with imaging reagents. Each nanoparticle measures less than five one-millionths of an inch in diameter -- about one-sixtieth that of a human red blood cell.

"We hypothesized that these particles, injected intravenously, would preferentially home in on tumors but not healthy brain tissue," said Gambhir, who is also a member of the Stanford Cancer Institute. "The tiny blood vessels that feed a brain tumor are leaky, so we hoped that the spheres would bleed out of these vessels and lodge in nearby tumor material." The particles' gold cores, enhanced as they are by specialized coatings, would then render the particles simultaneously visible to three distinct methods of imaging, each contributing uniquely to an improved surgical outcome.

One of those methods, magnetic resonance imaging, is already frequently used to give surgeons an idea of where in the brain the tumor resides before they operate. MRI is well-equipped to determine a tumor's boundaries, but when used preoperatively it can't perfectly describe an aggressively growing tumor's position within a subtly dynamic brain at the time the operation itself takes place.

The Gambhir team's nanoparticles are coated with gadolinium, an MRI contrast agent, in a way that keeps them stably attached to the relatively inert spheres in a blood-like environment. (In a 2011 study published in Science Translational Medicine, Gambhir and his colleagues showed in small animal models that nanoparticles similar to those used in this new study, but not containing gadolinium, were nontoxic.)

A second, newer method is photoacoustic imaging, in which pulses of light are absorbed by materials such as the nanoparticles' gold cores. The particles heat up slightly, producing detectable ultrasound signals from which a three-dimensional image of the tumor can be computed. Because this mode of imaging has high depth penetration and is highly sensitive to the presence of the gold particles, it can be useful in guiding removal of the bulk of a tumor during surgery.

The third method, called Raman imaging, leverages the capacity of certain materials (included in a layer coating the gold spheres) to give off almost undetectable amounts of light in a signature pattern consisting of several distinct wavelengths. The gold cores' surfaces amplify the feeble Raman signals so they can be captured by a special microscope.

To demonstrate the utility of their approach, the investigators first showed via various methods that the lab's nanoparticles specifically targeted tumor tissue, and only tumor tissue.

Next, they implanted several different types of human glioblastoma cells deep into the brains of laboratory mice. After injecting the imaging-enhancing nanoparticles into the mice's tail veins, they were able to visualize, with all three imaging modes, the tumors that the glioblastoma cells had spawned.

The MRI scans provided good preoperative images of tumors' general shapes and locations. And during the operation itself, photoacoustic imaging permitted accurate, real-time visualization of tumors' edges, enhancing surgical precision.

But neither MRI nor photoacoustic imaging by themselves can distinguish healthy from cancerous tissue at a sufficiently minute level to identify every last bit of a tumor. Here, the third method, Raman imaging, proved crucial. In the study, Raman signals emanated only from tumor-ensconced nanoparticles, never from nanoparticle-free healthy tissue. So, after the bulk of an animal's tumor had been cleared, the highly sensitive Raman-imaging technique was extremely accurate in flagging residual micrometastases and tiny fingerlike tumor projections still holed up in adjacent normal tissue that had been missed on visual inspection. This, in turn, enabled these dangerous remnants' removal.

"Now we can learn the tumor's extent before we go into the operating room, be guided with molecular precision during the excision procedure itself and then immediately afterward be able to 'see' once-invisible residual tumor material and take that out, too," said Gambhir, who suggested that the nanoparticles' propensity to heat up on photoacoustic stimulation, combined with their tumor specificity, might also make it possible for them to be used to selectively destroy tumors. He also expressed optimism that this kind of precision could eventually be brought to bear on other tumor types.

The study was funded by the National Institutes of Health, the National Cancer Institute's Center for Cancer Nanotechnology Excellence, the Ben and Catherine Ivy Foundation, the Canary Foundation and the Leon Levy Foundation.

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'Nanobubbles' Plus Chemotherapy Equals Single-Cell Cancer Targeting

Dmitri Lapotko. (Credit: Jeff Fitlow/Rice University)

Science Daily  — Using light-harvesting nanoparticles to convert laser energy into "plasmonic nanobubbles," researchers at Rice University, the University of Texas MD Anderson Cancer Center and Baylor College of Medicine (BCM) are developing new methods to inject drugs and genetic payloads directly into cancer cells. In tests on drug-resistant cancer cells, the researchers found that delivering chemotherapy drugs with nanobubbles was up to 30 times more deadly to cancer cells than traditional drug treatment and required less than one-tenth the clinical dose.

"We are delivering cancer drugs or other genetic cargo at the single-cell level," said Rice's Dmitri Lapotko, a biologist and physicist whose plasmonic nanobubble technique is the subject of four new peer-reviewed studies, including one due later this month in the journal Biomaterials and another published April 3 in the journal PLoS ONE. "By avoiding healthy cells and delivering the drugs directly inside cancer cells, we can simultaneously increase drug efficacy while lowering the dosage," he said.

Delivering drugs and therapies selectively so they affect cancer cells but not healthy cells nearby is a major obstacle in drug delivery. Sorting cancer cells from healthy cells has been successful, but it is both time-consuming and expensive. Researchers have also used nanoparticles to target cancer cells, but nanoparticles can be taken up by healthy cells, so attaching drugs to the nanoparticles can also kill healthy cells.

Rice's nanobubbles are not nanoparticles; rather, they are short-lived events. The nanobubbles are tiny pockets of air and water vapor that are created when laser light strikes a cluster of nanoparticles and is converted instantly into heat. The bubbles form just below the surface of cancer cells. As the bubbles expand and burst, they briefly open small holes in the surface of the cells and allow cancer drugs to rush inside. The same technique can be used to deliver gene therapies and other therapeutic payloads directly into cells.

This method, which has yet to be tested in animals, will require more research before it might be ready for human testing, said Lapotko, faculty fellow in biochemistry and cell biology and in physics and astronomy at Rice.

The Biomaterials study due later this month reports selective genetic modification of human T-cells for the purpose of anti-cancer cell therapy. The paper, which is co-authored by Dr. Malcolm Brenner, professor of medicine and of pediatrics at BCM and director of BCM's Center for Cell and Gene Therapy, found that the method "has the potential to revolutionize drug delivery and gene therapy in diverse applications."

"The nanobubble injection mechanism is an entirely new approach for drug and gene delivery," Brenner said. "It holds great promise for selectively targeting cancer cells that are mixed with healthy cells in the same culture."

Lapotko's plasmonic nanobubbles are generated when a pulse of laser light strikes a plasmon, a wave of electrons that sloshes back and forth across the surface of a metal nanoparticle. By matching the wavelength of the laser to that of the plasmon, and dialing in just the right amount of laser energy, Lapotko's team can ensure that nanobubbles form only around clusters of nanoparticles in cancer cells.

Using the technique to get drugs through a cancer cell's protective outer wall, or cell membrane, can dramatically improve the drug's ability to kill the cancer cell, as shown by Lapotko and MD Anderson's Xiangwei Wu in two recent studies, one in Biomaterials in February and another in Advanced Materials in March.

"Overcoming drug resistance represents one of the major challenges in cancer treatment," said Wu. "Targeting plasmonic nanobubbles to cancer cells has the potential to enhance drug delivery and cancer-cell killing."

To form the nanobubbles, the researchers must first get the gold nanoclusters inside the cancer cells. The scientists do this by tagging individual gold nanoparticles with an antibody that binds to the surface of the cancer cell. Cells ingest the gold nanoparticles and sequester them together in tiny pockets just below their surfaces.

While a few gold nanoparticles are taken up by healthy cells, the cancer cells take up far more, and the selectivity of the procedure owes to the fact that the minimum threshold of laser energy needed to form a nanobubble in a cancer cell is too low to form a nanobubble in a healthy cell

The research is funded by the National Institutes of Health.

Nanotechnology Used to Hunt for Hidden Pathogens

Isolation of MAP requires collection of infected white bloods cells from blood samples via centrifugation. For direct nPCR analysis, DNA directly isolated from white blood cells is purified in multiple steps prior to amplification and detection by gel electrophoresis. Meanwhile, culture-based nPCR requires the growth of MAP in specialized liquid media for 12 weeks, followed by DNA isolation before nPCR. Hybridizing magnetic relaxation sensors (hMRS) can detect MAP DNA in minimally processed blood samples via changes in magnetic signal (”¤2) in 1 hour, as opposed to 24 hours for direct nPCR and 12 weeks for culture nPCR. (Credit: Kaittanis et al., PLoS ONE, 2012; DOI 10.1371/journal.pone.0035326)                           Science Daily — Researchers at the University of Central Florida have developed a novel technique that may give doctors a faster and more sensitive tool to detect pathogens associated with inflammatory bowel disease, including Crohn's disease.

The microbes reappear years later and can cause serious health problems such as seen in tuberculosis cases. Current testing methods to find these hidden microbes exist, but require a long time to complete and often delay effective treatment for weeks or even months.The new nanoparticle-based technique also may be used for detection of other microbes that have challenged scientists for centuries because they hide deep in human tissue and are able to reprogram cells to successfully evade the immune system.

UCF Associate Professor J. Manuel Perez and Professor Saleh Naser and their research team have developed a method using nanoparticles coated with DNA markers specific to the elusive pathogens. The technique is effective and more accurate than current methods at picking up even small amounts of a pathogen. More important, it takes hours instead of weeks or months to deliver results, potentially giving doctors a quicker tool to help patients.

"Our new technique has surpassed traditional molecular and microbiological methods," said Naser, a professor at the UCF College of Medicine. "Without compromising specificity or sensitivity, the nano-method produced reliable and accurate results within hours compared to months."

The group's translational research works was recently published in the journal PLoS ONE.

The team created hybridizing magnetic relaxation nanosensors (hMRS) that can fish out and detect minuscule amounts of DNA from pathogens hiding within a patient's cells. The hair-thin hMRS are composed of a polymer-coated iron oxide nanoparticle and are chemically modified to specifically bind to a DNA marker that is unique to a particular pathogen.

When the hMRS bind to the pathogen's DNA, a magnetic resonance signal is detected, which is amplified by the water molecules that surround the nanoparticle. Then the researcher can read the change in the magnetic signature on a computer screen or portable electronic device, such as a smartphone, and determine whether the sample is infected with a particular pathogen.

The researchers used Mycobacterium avium spp. paratuberculosis (MAP), a pathogen that has been implicated in the cause of Johne's disease in cattle and Crohn's disease in humans, to test out their technique. They used a large number of blood and biopsy tissue samples from patients with Crohn's disease and meat samples from cattle with Johne's disease.

"It is all about giving medical professionals easy and reliable tools to better understand the spread of a disease, while helping people get treatment faster," said Perez, who works at UCF's Nanoscience Technology Center. "That's my goal. And that's where nanotechnology really has a lot to offer, particularly when the technology has been validated using clinical, food and environmental samples as is in our case."

The National Institute of General Medical Sciences (NIGMS), which is a part of the National Institutes of Health, and funded the research, said this kind of basic research can provide the foundation for medical breakthroughs.

"Just last year, Dr. Perez and his team unexpectedly discovered the DNA binding property of their magnetic nanosensors, and now they have shown that it may become the basis for a rapid, sensitive lab test for hard-to-measure bacteria and viruses in patient samples," said Janna Wehrle, Ph.D., of NIGMS. "This is a wonderful example of how quickly an advance can move from the research bench to meet an important clinical need."

Charalambos Kaittanis, who received his doctoral degree at UCF and worked as a postdoctoral Research Associate under Perez, has lead the experimental work in this study. Kaittanis is now a research fellow at Memorial Sloan-Kettering Cancer Center.

Gold helps deliver cancer drugs

THE UNIVERSITY OF SYDNEY

The researchers suggest the effectiveness of many cancer drugs could be significantly improved by gold nanoparticles. Image: idal/iStockphoto Gold nanoparticles can be used as delivery vehicles for platinum anticancer drugs, improving targeting and uptake into cells, according to research published in the international journalInorganic Chemistry. Researchers at the University of Sydney's Faculty of Pharmacy investigated the appropriateness of different sized gold nanoparticles as components of platinum-based drug delivery systems such as cisplatin. The researchers studied the cancer drug's controlled synthesis, reproducibility, consistency of drug loading and stability. According to Dr Nial Wheate, senior lecturer in pharmaceutical chemistry and leader of the project, the effectiveness of the cancer drug cisplatin could be significantly improved by gold nanoparticles, which selectively pick up and drive the platinum-based drug into solid cancer tumours. Dr Wheate says the team conducted multiple testing regimes on the gold nanoparticles: "For any new drug to get approval for human clinical trials, it must demonstrate not only efficiency but also the capability of being reproducibly manufactured and stable in storage," he says. "Developing and making a drug is a lot like building and designing a car. You have to test and retest it for durability and all the safety features. "Previously, we have shown that platinum drugs can be attached to gold nanoparticles and that cellular uptake and effectiveness levels are greatly improved. "But we needed to be sure that the benefits of the drug would be consistent. We believed when developing gold nanoparticles as platinum drug-delivery vehicles, it was essential they were reproducible and stable to ensure consistent and safe doses were administered to patients." Cisplatin is the leading metallodrug used in the systemic treatment of solid tumours. "To date, however, its use has been limited by severe toxic side effects, attributed to the indiscriminate accumulation of the drug in both normal and cancerous tissue," says Dr Wheate. Cisplatin is currently used to treat several types of cancers including testicular, ovarian, bladder, oesophageal, lung, and cervical cancers and melanomas. Editor's Note: Original news release can be found here.

Better solar cell developed

FLINDERS UNIVERSITY

Imagine a world where the windows of high-rise office buildings are influential energy producers, offering its inhabitants much more than some fresh air, light and a view. For the past four years, a team of researchers from Flinders University has been working to make this dream a reality – and now the notion of solar-powered windows could be coming to a not-too-distant future near you. As part of his just-completed PhD, Dr Mark Bissett from the School of Chemical and Physical Sciences has developed a revolutionary solar cell using carbon nanotubes. Carbon nanotubes are a promising alternative to traditional silicon-based solar cells, which are cheaper and more efficient than their energy-sapping silicon counterparts. “Solar power is the most expensive type of renewable energy. The silicon solar cells we see on peoples’ roofs are costly to produce and use a lot of electricity to purify,” Dr Bissett said. “The overall efficiency of silicon solar cells is about 10 per cent, and even when they’re operating at optimal efficiency, it could take eight to 15 years to make back the energy that it took to produce them in the first place because they’re produced using fossil fuels,” he said. Dr Bissett said the new, low-cost carbon nanotubes are transparent, meaning they can be 'sprayed' onto windows without blocking light, and they are also flexible so they can be weaved into a range of materials. One is fabric – a concept already being explored by advertising companies. While the amount of power generated by solar windows would not be enough to completely offset the energy consumption of a standard office building, Dr Bissett said they still had many financial and environmental advantages. “In a new building, or one where the windows are being replaced anyway, adding transparent solar cells to the glass would be a relatively small cost since the cost of the glass, frames, and installation would be the same with or without the solar component,” Dr Bissett said. “It’s basically like tinting the windows except they’re able to produce electricity, and considering office buildings don’t have a lot of roof space for solar panels, it makes sense to utilise the many windows they have instead.” Dr Bissett said the technology mimics photosynthesis, the process whereby plants obtain energy from the sun. “A solar cell is created by taking two sheets of electrically conductive glass and sandwiching a layer of functionalised single-walled carbon nanotubes between the glass sheets,” he said. “When light shines on the cell, electrons are generated within the carbon nanotubes, which can be used to power electrical devices.” Although small prototypes have been developed in the lab, he said the next step would be to test the carbon cells on an 'industrial stage'. The material could be on the market within 10 years if all goes to plan. “When we first started the research, we had no idea if it would work because we were the first in the world to try it, so it’s pretty exciting that we’ve proved the concept, and hopefully, it will be commercially available in a few years,” Dr Bissett said. Dr Bissett is a winner of Flinders's inaugural Best Student Paper Award, a now annual program which aims to recognise excellence in student research across the University. Editor's Note: Original news release can be found here.

Influence of nanoparticles on nutrient absorption

 by Biomechanism 

Nanoparticles are everywhere. From cosmetics and clothes, to soda and snacks. But as versatile as they are, nanoparticles also have a downside, say researchers at Binghamton University and Cornell University in a recent paper published in the journal Nature Nanotechnology. These tiny particles, even in low doses, could have a big impact on our long-term health.

According to lead author of the article, Gretchen Mahler, assistant professor of bioengineering at Binghamton University, much of the existing research on the safety of nanoparticles has been on the direct health effects. But what Mahler, Michael L. Shuler of Cornell University and a team of researchers really wanted to know was what happens when someone gets constant exposure in small doses – the kind you’d get if you were taken a drug or supplement that included nanoparticles in some form.

“We thought that the best way to measure the more subtle effects of this kind of intake was to monitor the reaction of intestinal cells,” said Mahler. “And we did this in two ways – in vitro, through human intestinal-lining cells that we had cultured in the lab; and in vivo, through the intestinal linings of live chickens. Both sets of results pointed to the same thing – that exposure to nanoparticles influences the absorption of nutrients into the bloodstream.”

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This figure shows 50 nm carboxylated polystyrene nanoparticles (green) interacting with a cell culture model of the intestinal epithelium (red). Oral exposure to these particles was shown to affect iron transport. Credit: Nature Nanotechnology

The uptake of iron, an essential nutrient, was of particular interest due to the way it is absorbed and processed through the intestines. The way Mahler and the team tested this was to use polystyrene nanoparticles because of its easily traceable fluorescent properties.

“What we found was that for brief exposures, iron absorption dropped by about 50 percent,” said Mahler. “But when we extended that period of time, absorption actually increased by about 200 percent. It was very clear – nanoparticles definitely affects iron uptake and transport.”

While acute oral exposure caused disruptions to intestinal iron transport, chronic exposure caused a remodeling of the intestinal villi – the tiny, finger-like projections that are vital to the intestine’s ability to absorb nutrients – making them larger and broader, thus allowing iron to enter the bloodstream much faster.

“The intestinal cells are a gateway that ingested nanoparticles must go through to get to the body,” said Mahler. “We monitored iron absorption both in vivo and in vitro and found that the polystyrene nanoparticles affected the absorption process and caused a physiological response.”

The next step for Mahler and the team is to take a look at whether similar disruptions in nutrient absorption could be possible in other inorganic elements such as calcium, copper and zinc. Also on the research agenda is the reaction of other nutrients such as fat-soluble vitamins A, D, E and K. And chickens and their intestines will definitely be part of this next phase of the study.

“The gastrointestinal tract of chickens have very similar features to that of humans,” said Mahler. “We can learn a great deal from the way chicken tissue works which means we can make better predictions about how humans will react.”

And humans certainly consume enough nanoparticles – about 100 trillion of them every day. Their ultra-small size and amazing qualities makes them increasingly common in food and pharmaceutical products. Although the impact of chronic exposure remains somewhat unknown, the ingestion of dietary particles is thought to promote a range of diseases, including Crohn’s disease.

With so many nanomaterials under development and with so much yet to be learned about nanoparticle toxicity and potential human tissue reactivity, Mahler and the team are hoping that their work, particularly the in vitro model, will provide an effective low-cost screening tool.

Solved: Mystery of the Nanoscale Crop Circles

When a thin layer of gold anneals on top of a silicon wafer coated with native silicon oxide, randomly distributed pools of eutectic alloy quickly form – and then go through a rapid series of strange changes, leaving behind bare silicon-dioxide circles surrounded by debris. Each denuded circle reveals a perfect square at its center. The area shown is about 107 by 155 micrometers (millionths of a meter). (Credit: Image courtesy of DOE/Lawrence Berkeley National Laboratory)                          Science Daily  — Almost three years ago a team of scientists at the U.S. Department of Energy's Lawrence Berkeley National Laboratory (Berkeley Lab) was performing an experiment in which layers of gold mere nanometers (billionths of a meter) thick were being heated on a flat silicon surface and then allowed to cool. They watched in surprise as peculiar features expanded and changed on the screen of their electron microscope, finally settling into circles surrounded by irregular blisters.

Until recently the cause of these strange formations remained a mystery. Now theoretical insights have explained what's happening, and the results have been published online by Physical Review Letters.The circles varied in diameter up to a few millionths of a meter, and in the center of each was a perfect square. The mysterious patterns were reminiscent of nothing so much as so‑called "alien" crop circles.

Eagerly melting alloys

When two solids are combined in just the right proportions, changes in chemical bonding may produce an alloy that melts at a temperature far lower than either can melt by itself. Such an alloy is called eutectic, Greek for "good melting." The eutectic alloy of gold and silicon -- 81 percent gold and 19 percent silicon -- is especially useful in processing nanoscale semiconductors such as nanowires, as well as for device interconnections in integrated circuits; it liquefies at a modest 363˚ Celsius, far lower than the melting point of either pure gold, 1064°C, or pure silicon, 1414°C.

"Gold-silicon eutectic liquid can safely solder chip layers together or form microscopic conducting wires, by flowing into channels in the substrate without burning up the surroundings," says Berkeley Lab's Junqiao Wu. "It's particularly interesting for processing nanoscale materials and devices." Wu cites the example of silicon nanowires, which can be grown from beads of eutectic liquid that form from droplets of gold. The beads catalyze the deposition of silicon from a chemical vapor and ride atop continually lengthening nanowire whiskers.

Understanding just how and why this happens has been a challenge. Although eutectic alloys are well studied as solids, the liquid state presents more obstacles, which are particularly formidable at the nanoscale because of greatly increased surface tension -- the same surface forces that make it difficult to form ultra-thin films of water, for example, because they pull the water into droplets. At smaller scales the ratio of surface area to bulk increases markedly, and nanoscale structures have been described as virtually "all surface."

These are the conditions that the team led by Wu, who is a faculty scientist in Berkeley Lab's Materials Sciences Division and a professor in the Department of Materials Science and Engineering at the University of California at Berkeley, set out to examine, by creating the thinnest possible films of gold-silicon eutectic alloys. The researchers did so by starting with a substrate of pure silicon, on whose flat surface an extremely thin barrier layer (two nanometers thick) of silicon dioxide had formed. On this surface they laid layers of pure gold, varying the thickness from one trial to the next between just a few nanometers to a hefty 300 nanometers. The silicon dioxide barrier prevented the pure silicon from mixing with the gold.

The next step was to heat the layered sample to 600 °C for several minutes -- not hot enough to melt the gold or silicon but hot enough to cause naturally existing pinholes in the thin silicon dioxide layer to enlarge into small weak spots, through which pure silicon could come in contact with the overlying gold. At the high temperature, silicon atoms quickly diffused out of the substrate and into the gold, forming a layer of eutectic gold-silicon alloy nearly the same thickness as the original gold and spreading in a virtually perfect circle from the central pinhole.

When the circular disk of eutectic alloy got large enough it suddenly broke up, disrupted by the high surface energy of the gold-silicon eutectic liquid. The debris was literally pulled to the edges of the disk, piling up around it to leave a central denuded zone of bare silicon dioxide.

In the center of the denuded zone, a perfect square of gold and silicon remained.

Chemistry and crystallography, not aliens

The researchers' most surprising discovery was that the thinner the original gold layer, the faster the eutectic circles expanded. The reaction rate when the gold layers were only 20 nanometers thick was more than 20 times faster than when the layers were 300 nanometers thick. And while at first glance the dimensions of the gold and silicon squares inside the circular denuded zones seemed variable, there was in fact a strict relation between the size of the square and the size of the circle: the radius of the circle was always the length of the square raised to the power of 3/2.

How did the squares get there in the first place? They originated as weak spots that were the sources of the spreading eutectic gold-silicon circles; when the circular eutectic was ruptured the squares filled with the same eutectic, which remained at the centers of the denuded zones. As they cooled, the gold and silicon within the squares separated, leaving sharply defined edges that were pure silicon; the centers were more roughly outlined squares of pure gold.

By slicing through the silicon/silicon dioxide/gold layercake and looking sideways at the structures with an electron microscope, the researchers found that the surface squares were the bases of inverted pyramids, resembling teeth penetrating the thin silicon dioxide layer and embedded in the silicon wafer. The squares were square, in fact, because of the silicon's orientation: the substrate had been cut along the crystal plane that defined the base. The four triangular sides of the pyramids lay along the low-energy planes of the crystal lattice and were defined by their intersections.

What began as a puzzling phenomenon reminiscent of "The X Files," if on a considerably smaller scale than the cosmic, the mystery of the "nanoscale crop circles" eventually yielded to careful observation and theoretical analysis -- despite the obstacles posed by high temperatures, nanoscale sizes, instabilities of the liquid state, and extremely rapid time scales.

"We found that the reaction rate in forming small-sized gold-silicon eutectic liquids -- and perhaps in many other eutectics as well -- is dominated by the thickness of the reacting layers," says Wu. "This discovery may provide new routes for the engineering and processing of nanoscale materials."

Recharge Your Cell Phone With a Touch? New Nanotechnology Converts Body Heat Into Power

Graduate student Corey Hewitt works with a sample of thermoelectric fabric in the Nanotechnology lab. (Credit: Image courtesy of Wake Forest University)                                    Science Daily  — Never get stranded with a dead cell phone again. A promising new technology called Power Felt, a thermoelectric device that converts body heat into an electrical current, soon could create enough juice to make another call simply by touching it.

Their research appears in the current issue of Nano Letters, a leading journal in nanotechnology.Developed by researchers in the Center for Nanotechnology and Molecular Materials at Wake Forest University, Power Felt is composed of tiny carbon nanotubes locked up in flexible plastic fibers and made to feel like fabric. The technology uses temperature differences -- room temperature versus body temperature, for instance -- to create a charge.

"We waste a lot of energy in the form of heat. For example, recapturing a car's energy waste could help improve fuel mileage and power the radio, air conditioning or navigation system," says researcher and Wake Forest graduate student Corey Hewitt. "Generally thermoelectrics are an underdeveloped technology for harvesting energy, yet there is so much opportunity."

Potential uses for Power Felt include lining automobile seats to boost battery power and service electrical needs, insulating pipes or collecting heat under roof tiles to lower gas or electric bills, lining clothing or sports equipment to monitor performance, or wrapping IV or wound sites to better track patients' medical needs.

"Imagine it in an emergency kit, wrapped around a flashlight, powering a weather radio, charging a prepaid cell phone," says David Carroll, director of the Center for Nanotechnology and Molecular Materials. "Power Felt could provide relief during power outages or accidents."

Cost has prevented thermoelectrics from being used more widely in consumer products.

Standard thermoelectric devices use a much more efficient compound called bismuth telluride to turn heat into power in products including mobile refrigerators and CPU coolers, but researchers say it can cost $1,000 per kilogram. Like silicon, they liken Power Felt's affordability to demand in volume and think someday it could cost only $1 to add to a cell phone cover.

Currently, 72 stacked layers in the fabric yield about 140 nanowatts of power. The team is evaluating several ways to add more nanotube layers and make them even thinner to boost the power output.

Although there's more work to do before Power Felt is ready for market, Hewitt says, "I imagine being able to make a jacket with a completely thermoelectric inside liner that gathers warmth from body heat, while the exterior remains cold from the outside temperature. If the Power Felt is efficient enough, you could potentially power an iPod, which would be great for distance runners. It's definitely within reach."

Nanoparticles May Enhance Cancer Therapy

In the new study by Rice University and MD Anderson, mice with dual subcutaneous tumors – the left one EGFR-negative, the right one EGFR-positive – were treated with the new Cet/PTX/PEG-HCC mixture, a carbon nanoparticle-based chemotherapeutic drug tuned to target EGFR-positive tumors. Treatment over 30 days proved highly effective in killing the right-side tumors, underscoring the efficacy of the targeted approach. (Credit: E. Loïc Samuel/Rice University)                                  ScienceDaily (Feb. 16, 2012) — A mixture of current drugs and carbon nanoparticles shows potential to enhance treatment for head-and-neck cancers, especially when combined with radiation therapy, according to new research by Rice University and the University of Texas MD Anderson Cancer Center.

A paper on the research was published this month in the American Chemical Society journal ACS Nano.The work blazes a path for further research into therapy customized to the needs of individual patients. The therapy uses carbon nanoparticles to encapsulate chemotherapeutic drugs and sequester them until they are delivered to the cancer cells they are meant to kill.

The new strategy by Rice chemist James Tour and Jeffrey Myers, a professor of head-and-neck surgery at MD Anderson, combines paclitaxel (PTX) and Cetuximab (Cet) with hydrophilic carbon clusters functionalized with polyethylene glycol, known as PEG-HCC.

Cetuximab, the targeting agent, is a humanized monoclonal antibody that binds exclusively to the epidermal growth factor receptor (EGFR), a cell-surface receptor overexpressed by 90 percent of head-and-neck squamous cell cancers. Paclitaxel, an active agent in chemotherapy, is used to treat lung, ovarian, breast and head-and-neck cancers. In combination, they have the ability to target and attack cancerous cells.

Because paclitaxel is hydrophobic -- it won't mix with water -- the substances are generally combined with Cremophor EL, a castor oil-based carrier that allows the compound marketed as Taxol to be delivered intravenously to patients.

Tour, Myers and their associates have found a simple way to mix PTX and Cetuximab with carbon clusters that adsorb the active ingredients. The new compound is water-soluble and is more effective at targeting tumors than Taxol while avoiding the toxic effects of paclitaxel and Cremophor on adjacent healthy cells, they wrote.

"It's very common to administer cortical steroids to limit the allergic response to Cremophor EL," said Tour, Rice's T.T. and W.F. Chao Chair in Chemistry as well as a professor of mechanical engineering and materials science and of computer science.

Tour said the Cet/PTX/PEG-HCC elements combine easily. "We show in the paper that when we take paclitaxel up in our hydrophilic carbon clusters, we can deliver these just as well as commercial Taxol.

"But you can never break into a market with something that's just as good as what's already out there. You have to be substantially better. The beauty of what we're doing is that we can potentially use a much smaller amount of the drug for chemotherapy. Just eliminating the Cremophor is a real advantage," he said.

Tour noted a recently approved chemotherapy drug that combines paclitaxel with albumin nanoparticles, Abraxane, also shows promise. "That works well, but it still only has about 10 percent of the market after six or seven years of use," he said.

Myers, the Hubert L. and Olive Stringer Distinguished Professor in Cancer Research at MD Anderson, said combining Cet/PTX/PEG-HCC and radiation therapy in tests on mice showed a significant boost in killing tumors. "Our hypothesis is that PTX, the chemotherapy drug, sensitizes the cancer cells to the effects of radiation and the Cetuximab/PEG-HCC increases the delivery of PTX to the cancer cells," he said.

Unlike Cremophor, Tour said, the enhanced carbon clusters are nontoxic. Biodistribution and toxicity studies showed the "large majority" of PEG-HCCs are excreted through the kidneys, while trace amounts in the livers and spleens of mice tested showed no damage to the organs.

The strategy sprang from conversations between Tour and Rice chemist and Nobel laureate Richard Smalley, who died of leukemia in 2005. "I was sitting with Rick at MD Anderson while he was being treated, and we got to talking about using carbon particles for delivery as carbon-based carriers.

"But we had nothing specific," Tour said. "I started to work on this without funding, and shortly after Rick's passing in October 2005, I met with Jeff Myers."

"I wanted to establish a multidisciplinary program to study nanoparticle-based therapeutics for cancer in general, and more specifically, head-and-neck cancer," Myers said. "At the time, Dr. Garth Powis (professor and chair of the Department of Experimental Therapeutics at MD Anderson) directed me to Dr. Mauro Ferrari (now president of The Methodist Hospital Research Institute and an adjunct professor of bioengineering at Rice), who ultimately put me in touch with Dr. Tour.

"His enthusiasm for science and willingness to further explore the potential of carbon nanoparticles to treat cancer patients was apparent right away, and we launched a collaborative effort that has been quite productive," he said.

Myers is pleased with what the team has accomplished so far. "This collaborative work has 'proved the principle' that carbon nanoparticles can be used to non-covalently link a chemotherapeutic drug with a targeting antibody that can deliver the drug specifically to a cancer cell," he said. "This principle could be used to deliver other drugs to other types of cells through specific targeting of cell surface receptors as a method of increasing the therapeutic ratio.

"Though I am not an expert in these other areas, this could potentially have applications in infectious diseases, neurologic disorders and cardiovascular illnesses," he said.

Tour sees potential for clinical uses of PEG-HCCs for brain cancer and traumatic brain injuries as well as chemotherapy, but acknowledged the introduction of such drugs for human use is a long way off. "To get a drug through all the different phases, including trials, typically takes 12 to 14 years and about $1.25 billion," he said. "That can sometimes be expedited through experimental trials with patients who have no other options, but it's still a long and expensive haul."

Still, he said the new work is a strong step in the right direction. "This paper is the highlight of six years of research," he said. "It all came together. This is the crescendo, right here."

The paper's lead authors are Daisuke Sano, a former postdoctoral fellow at MD Anderson, now at Yokohama City University Graduate School of Medicine in Japan, and Jacob Berlin, a researcher in Tour's Rice lab and now a professor at City of Hope Hospital, Duarte, Calif. Co-authors are Rice alumnus Tam Pham and graduate student Daniela Marcano; and Ge Zhou, an assistant professor in the Department of Head and Neck Surgery, David Valdecanas, laboratory coordinator in experimental radiation oncology, and Luka Milas, a professor of experimental radiation oncology, all at MD Anderson.

The research was supported by The Alliance for NanoHealth through a Department of Defense subcontract from the University of Texas Health Science Center at Houston; the Mission Connect Mild Traumatic Brain Injury Consortium, also funded by the Department of Defense; the Nanoscale Science and Engineering Initiative of the National Science Foundation; the MD Anderson Cancer Center PANTHEON Program; a National Institutes of Health Cancer Center Support Grant; and an MD Anderson Cancer Center Support Grant.

Cinnamon Could Replace Harsh Chemicals To Produce Gold Nanoparticles, Researchers Say

By Rebecca Boyle

Cinnamon Nanotubes? Cinnamon can be used as a replacement for toxic chemicals in the production of gold nanoparticles, scientists say. aziatische-ingredienten.nl

A humble spice found in nearly every kitchen could yield a safer, simpler way to produce gold nanoparticles, according to a new study. Researchers say the cinnamon-infused particles can even be used to fight cancer.

Gold nanoparticles are heralded for their potential to detect tumors, search for oil, light the streets and cure diseases, but their production requires dangerous toxic chemicals. There are several ways to produce gold particles, but most involve dissolving chloroauric acid, also called gold salts, in liquid and adding chemicals to precipitate gold atoms. Common mixtures include sodium citrates, sodium borohydride (also used to bleach wood pulp) and ammonium compounds, all of which can be toxic to humans and the environment.

Hoping to promote green nanotechnology, researchers at the University of Missouri mixed gold salts with cinnamon instead and stirred the mixture in water. The combination produced gold nanoparticles and phytochemicals, an active chemical in cinnamon. When combined with the nanoparticles, the phytochemicals can enter cancer cells and destroy them or help image them for more accurate medical procedures.

“Our gold nanoparticles are not only ecologically and biologically benign, they also are biologically active against cancer cells,” said Kattesh Katti, a professor of radiology and physics at the University of Missouri School of Medicine.

The process uses no electricity and no chemicals, other than the initial gold salts. The researchers reported their work in the journal Pharmaceutical Research.

Katti said cinnamon and other seeds, leaves and herbs could be used to convert metals into nanoparticles without using harsh chemicals.

“Our approach to ‘green’ nanotechnology creates a renaissance symbolizing the indispensable role of Mother Nature in all future nanotechnological developments,” he said.

[Eurekalert]