Georgia Institute of Technology

Nanoparticles Are Moving Us Toward a Cancer-Free World

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IN BRIEF
  • A new nanoparticle therapy that uses a minute gel pellet to deliver siRNA to cancer cells has reduced or eliminated carcinomas in in vivo tests in four mice.
  • The treatment is still in its very early stages, but joins a growing number of nanoparticle therapies looking to improve how we combat disease on a cellular level.

LOWERING DEFENSES

While some medical studies focus on developing completely new medicines and treatments for diseases, others attempt to improve existing options. In an attempt at the latter, researchers from the Georgia Institute of Technology have developed a new nanoparticle-based treatment that makes chemotherapy more effective.

Their treatment targets epidermal growth factor receptors (EGFRs). These cell structures are found in epithelial cells, which line the body’s organs. In a healthy cell, they jumpstart a variety of typical cellular functions, but in cancer cells, they are overproduced. “The problem is that because of this overexpression, many cellular functions, including cell replication and resistance to certain chemotherapy drugs, are dramatically cranked up,” says chief researcher John McDonald.

When its DNA is damaged beyond repair, a cell’s natural defense is to kill itself, a process called apoptosis. Elevated levels of EGFR thwart this function. Therefore, chemotherapy drugs that are designed to trigger apoptosis in cancerous cells become ineffective.

The Georgia Tech researchers developed a nanoparticle therapy that uses a minute gel pellet to deliver short interfering (si) RNA to cancer cells. This siRNA is able to prevent the cell from starting the process to produce the protein for EGFR. “We’re knocking down EGFR at the RNA level,” McDonald said. “Since EGFR is multi-functional, it’s not exactly clear which malfunctions contribute to ovarian cancer growth. By completely knocking out its production in ovarian cancer cells, all EGFR functions are blocked.”

SOME TIME COMING

The researchers were able to see the efficacy of their method by using it to treat ovarian cancer in mice. By combining their siRNA with the chemotherapy drug cisplatin, they were able to reduce resistance to the medication and drastically shrink carcinomas or even eliminate them altogether. The plan to use the same nanohydrogel with other kinds of RNA to treat different types cancers.

Right now, the treatment is still at its very early stages and thus far the only in vivo trials have been on four mice. The law requires many more trials that show the treatment’s efficacy on animals before the researchers can move on to preliminary human trials, so we won’t be seeing this method used on people for quite some time. For now, it joins the growing number of nanoparticle treatments that could one day deal the final blow to the big C.

Scientists have built the world’s thinnest electric generator – and it’s only one atom wide

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Researchers have created a graphene-like material that generates electricity every time its stretched, and could power the wearable technology of the future.

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Image: Rob Felt, Georgia Institute of Technology

Scientists from the Georgia Institute of Technology and Columbia Engineering in the US have shown they can generate electricity from a layer of material that’s just one atom thick. The generator is made from molybdenum disulphide (MoS2), which is a clear, flexible and extremely light material that opens up huge possibilities for the future of electricity generation.

The new electrical generator is an example of piezoelectricity, or electricity that’s generated from pressure. Piezoelectric materials have huge potential to be used to create materials that can charge devices, such as footwear that powers an iPod. But until now, scientists have struggled to make these materials thin and flexible enough to be practical.

However, it’s been predicted that a substance capable of forming single-atom-thick molecules, or two-dimensional layers, would be highly piezoelectric.

Now the scientists have proved that this is the case for the first time ever. Their results have beenpublished in Nature.

To test whether MoS2 would be piezoelectric on the atomic scale, the team flaked off extremely thin layers of MoS2 onto a flexible substrate with electrical contact.

Because of the way these flakes were created, each had a slightly different number of layers – for example, while some were just one-atom-thick, others were eight-atoms-thick.

The scientists tested the piezoelectric response of these flakes by stretching the material, and measuring the flow of electrons into an external circuit.

Interestingly, they discovered that when the material had an odd number of layers, it generated electricity when stretched. But when it had an even number of layers, there was no current generated.

A single one-atom-thick layer of the material was able to generate 15 megavolts of electricity when stretched.

They also found that as the number of layers increased, the amount of current generated decreased, until eventually the material got too thick and stopped producing any electricity at all.

Computational studies suggest that this is because the atomic layers all have random orientations, and they eventually cancel each other out.

The research team also arranged these one-atom-thick layers of MoS2 into arrays, and found that together they were capable of generating a large amount of electricity.

This suggests that they’re a promising candidate for powering nano electronics, and could be used to create wearable technologies.

“This material – just a single layer of atoms – could be made as a wearable device, perhaps integrated into clothing, to convert energy from your body movement to electricity and power wearable sensors or medical devices, or perhaps supply enough energy to charge your cell phone in your pocket,” said James Hone, professor of mechanical engineering at Columbia engineering and co-leader of the research,

Power from the sea?

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Triboelectric nanogenerator extracts energy from ocean waves.

As sources of renewable energy, sun and wind have one major disadvantage: it isn’t always sunny or windy. Waves in the ocean, on the other hand, are never still. American researchers are now aiming to use waves to produce energy by making use of contact electrification between a patterned plastic nanoarray and water. In the journal Angewandte Chemie, they have introduced an inexpensive and simple prototype of a triboelectric nanogenerator that could be used to produce energy and as a chemical or temperature sensor.

Power from the sea? Triboelectric nanogenerator extracts energy from ocean waves

The triboelectric effect is the build up of an electric charge between two materials through contact and separation – it is commonly experienced when removal of a shirt, especially in dry air, results in crackling. Zhong Lin Wang and a team at the Georgia Institute of Technology in Atlanta have previously developed a triboelectric generator based on two solids that produces enough power to charge a mobile telephone battery. However, high humidity interferes with its operation. How could this technology work with waves in water? The triboelectric effect is not limited to solids; it can also occur with liquids. The only requirement is that specific electronic levels of two substances are close enough together. Water just needs the right partner – maybe a suitable plastic.

As a prototype, the researchers made an insulated plastic tank, whose lid and bottom contain copper foil electrodes. Their system is successful because the inside of the lid is coated with a layer of polydimethylsiloxane (PDMS) patterned with tiny nanoscale pyramids. The tank is filled with deionized water. When the lid is lowered so that the PDMS nanopyramids come into contact with the water, groups of atoms in the PDMS become ionized and negatively charged. A corresponding positively charged layer forms on the surface of the water. The electric charges are maintained when the PDMS layer is lifted out of the water. This produces a potential difference between the PDMS and the water. Hydrophobic PDMS was chosen in order to minimize the amount of water clinging to the surface; the pyramid shapes allow the water to drop off readily. Periodic raising and lowering of the lid while the electrodes are connected to a rectifier and capacitor produces a direct current that can be used to light an array of 60 LEDs. In tests with salt water, the generator produced a lower output, but it could in principle operate with seawater.

The current produced decreases significantly as temperature increases, which could allow this device to be used as a . It also decreases when ethanol is added to the , which suggests potential use of the system as a chemical sensor. By attaching probe molecules with specific binding partners, it may be possible to design sensors for biomolecules.

Under the skin of intradermal vaccines.

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Needleless vaccines may immunize patients more efficiently and effectively than injections. But are these new technologies ready for prime time?

At a makeshift clinic in southern Cambodia, with cows lazing on the dirt outside, children take turns sitting in a blue plastic chair, bracing themselves for the sharp pain of a measles vaccine injection. However, time and time again, the children barely flinch, let alone cry. Throughout the morning, more than 200 children are vaccinated. The key to the efficient and tearless vaccination: no needles necessary.

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n this scene captured on video during a Cambodian measles vaccination program, a device called a jet injector shoots a high-speed jet of the drug into the skin. Unlike a typical needle syringe that sticks all of the way into muscle, this device never punctures the skin. The jet injector is just one of a number of technologies being developed to deliver vaccines to patients without using painful muscle-piercing needles: everything from patches with tens of thousands of microscopic needles that painlessly perforate the skin, to ultrasound pulses that temporarily “open” the skin for drug delivery, to special concoctions of drugs engineered to seep into the skin.

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A lack of pain isn’t the only advantage of such methods. Vaccines delivered using these technologies may be more effective than intramuscular injections and thus require less of the drug. Moreover, many of these technologies are easier to use in the developing world because they use vaccine formulations that don’t require refrigeration and can be administered with minimal training. The challenge is to make effective vaccines and also drive down the cost of the technologies to deliver them. “At this point, we have a good degree of confidence that we can hit those goals,” says biomedical engineer Mark Kendall of the University of Queensland, in Brisbane, Australia, who has pioneered one of the new delivery approaches.

 

Look Ma, No Pain

Any vaccine aims to set off a minor immune reaction to essentially teach the body how to fight off a pathogen. Ideally, when inactivated or dead microorganisms, or parts of pathogens, are injected as a vaccine, the immune system not only produces antibodies against that organism but will also “remember” to fight it in the future. If the bacterium or virus is encountered again, the immune system is able to fend it off more quickly and efficiently than before. Historically, vaccines have been given using needles and syringes or oral formulations. In addition, although some oral vaccines have been successful—like those against polio and cholera—many work less effectively because the digestive system breaks down the complex vaccine molecules before they can fully mobilize the immune system. Even injecting vaccines into muscles has started to seem misguided to some researchers.

“If you think about how your body is designed, the immune system is looking for pathogens that enter the body from the outside,” says biomedical engineer Mark Prausnitz of the Georgia Institute of Technology in Atlanta. “It’s not expecting a pathogen to pop into your muscle.”

With this in mind, Prausnitz is among a handful of researchers who are focusing on delivering vaccines to the outermost layers of the skin, which contain a different set of immune cells than muscles, so-called dendritic cells that act as sentinels against intruders from the environment. Prausnitz’s approach is based on something called a microneedle patch, which is far less painful than it sounds. “It’s a technically accurate [name],” says Prausnitz, “but marketing folks don’t like it much since it still has the word ‘needle’.”

Microneedle patches contain arrays of hundreds or thousands of tiny spikes, each around 750 microns long, about half the thickness of a dime. When a patch of microneedles is pressed onto a person’s skin, the microneedles are long enough to pierce the outermost layer of the skin and deliver the drug, but they don’t dig deep enough to hit blood vessels, or even pain receptors. Different researchers have developed different types of microneedles: some are solid metal or plastic and are coated in drug on the outside; others are hollow and contain a liquid vaccine inside.

The patch that Prausnitz has designed has solid—but dissolvable—microneedles made of a fabricated material containing cellulose and sugar molecules. The microneedles are coated with a dry powder form of a vaccine. In a liquid vaccine, proteins can lose their structure when the temperature fluctuates, requiring refrigeration. Dry powders, however, offer proteins more physical stability and don’t need refrigeration. When the microneedle patch is stuck onto someone’s arm, the needles penetrate the skin and begin dissolving, diffusing the drug into the skin. The team’s initial study of patches for an influenza vaccine has shown that almost 90% of the microneedle material dissolves within five minutes (1). The punctures made by the microneedles are so minuscule they can only be spotted with a microscope, and heal entirely within two hours of removing a patch (2).

At first, the success of microneedles was simply that they got a vaccine into the body. However, when researchers began comparing the effectiveness of microneedle-delivered vaccines with classic, intramuscular injections for the same vaccine, they started to notice other benefits. For example, Prausnitz’s team found that mice that were given flu vaccines using a microneedle patch had better and longer-lasting protection against the influenza virus than if they were vaccinated using intramuscular injections (3).

Although the scientific rationale for this increased efficacy is still being studied, researchers think it’s success might be because of the high numbers of dendritic cells in the skin that are uniquely receptive to vaccines. However, that’s not all. “What we’ve seen so far is that it’s not only the vaccine itself causing a response, but the physical actions of the projections as well,” says Kendall.

Around every microneedle that punctures the skin—and Kendall’s NanoPass patch has 20,000 microneedles per square centimeter—Kendall observed an increase in localized cell death. When cells die and release their contents, the immune system is alerted to the turmoil, causing immune molecules to flood the site. “The biology and engineering really feed off each other,” says Samir Mitagotri of the University of California at Santa Barbara. “Now that people have developed these technologies to deliver drugs, we’re asking questions we didn’t ask before: How does the skin heal? How does the immune system react?”

In a recent PNAS report, researchers from King’s College School of Medicine in London made inroads into understanding this biology when they followed the path of a live adenovirus injected into mice using a microneedle array (4). The virus, they found, moved through the epidermis into the deeper dermis, and interacted with dendritic cells there. The team discovered that a unique subset of dendritic cells, found only in the skin, were required to confer immunity after the vaccine.

Even as these questions continue to be studied, researchers are moving forward on applying microneedle patches to different applications. Prausnitz has tested his patch for not only influenza, but for vaccines against rotavirus (5) and measles (6). Now, he has a grant from the Gates Foundation to apply the technique to a polio vaccine. Kendall, who has launched Vaxxas, a company to market his Nanopatch microneedle patch, is focusing on delivering a human papillomavirus (HPV) vaccine. Many of his initial trials have been conducted in Papua New Guinea, which has one of the highest rates of HPV infections in the world but limited or no access to the current vaccine because of cost. This year, Kendall’s team shipped their patches across the ocean to Papua New Guinea, testing to see how they held up during shipping and at higher temperatures. They also noticed the ease with which people figured out how to use the patches. Kendall is also collaborating with Merck to study the delivery of other vaccines—both existing and new—using microneedle patches.

All Sound, No Fury

Other research teams have turned entirely away from puncturing skin, and are instead making gels that naturally seep into the skin. Existing drug patches—like those containing hormones for birth control or nicotine for smoking cessation—rely on the fact that small molecules with certain chemical properties will diffuse through the upper layers of the skin. However, vaccines contain larger, hydrophilic molecules, which don’t move smoothly through the outermost, hydrophobic layer of the skin.

“The patches that are already out there have a narrow range of drug properties. They are all small and hydrophobic and have a very easy time getting into the skin,” Mitagotri says. “So we want to know how we can expand that range of properties,” he adds.

Mitagotri screened a massive library of short proteins to find ones that are especially adept at moving through the skin, and has homed in on one that he thinks can help vaccines (7). Mitagotri’s dubbed it SPACE, for “skin penetrating and cell entering,” and found that when it’s attached to molecules that wouldn’t normally move through the skin, it helps transport them across. Now, he’s trying to figure out why SPACE slips through the skin so easily; he thinks that it may bind or associate with keratin, a key structural protein in skin. Mitagotri’s also on the lookout for other molecules, or other properties of molecules, that can chaperone drugs across the skin (8).

Meanwhile, at the Massachusetts Institute of Technology in Cambridge, chemical engineer Daniel Blankschtein is trying out yet another technique to get drugs into the skin: rather than make tiny holes in the skin using microneedles, he’s using ultrasound waves to make the skin temporarily more permeable so that vaccines can pass through unaided.

“If you don’t pretreat your skin with ultrasound, you’ll get negligible amounts of the drugs we study through,” says Carl Schoellhammer, a graduate student in Blankschtein’s laboratory. “But a few minutes of ultrasound pretreatment, and the underlying skin can then take up the drug in meaningful amounts,” he says.

Ultrasound causes tiny air bubbles to form in the outermost layer of skin. As the bubbles grow, they become unstable and implode. This causes tiny abrasions, temporarily weakening the skin and making it easier for drugs to slip in.

Blankschtein and Schoellhammer have discovered a way to maximize this permeability. Low-frequency ultrasound tends to make bubbles more unstable, causing them to implode, whereas high-frequency ultrasound leads to more bubbles. By combining the two, the researchers found that they can create both more bubbles and more implosions. Glucose applied to pig skin after the dual treatment was absorbed 10-times better than when they used a single frequency of ultrasound (9).

Now, Blankschtein and Schoellhammer intend to test the system in humans and with vaccines. Like microneedles, an ultrasound could both help deliver the drug and recruit immune molecules to the site of vaccination by abrading the skin. Furthermore, ultrasound could be easily applied to vaccination efforts in the developing world. Minimal training is needed to use handheld ultrasound devices, and vaccines can be stored and transported as gels, which are more stable than liquids in the absence of refrigeration.

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Silicon Salvation

Exciting as these ideas are, they need to be commercially viable. Kendall hopes to make the Nanopatch competitive by making his microneedle patch from silicon wafers, which are already mass-produced for other purposes. “We’re using a deep-etching process highly utilized by the semiconductor industry,” says Kendall. He estimates that producing five million such patches a year would bring the cost per application down to less than a dollar.

Jet injectors of the type used in the Cambodia measles vaccination program would also be easy to scale up. Jet injectors were popular for mass vaccinations of smallpox and other pathogens in the mid-20th century, but were designed to be reused in patient after patient, so concerns about cross-contamination led to a decline in their use. However, new jet injectors, such as the PharmaJet Stratis used in Cambodia, have disposable components, alleviating such concerns. Darin Zehrung, the team leader of vaccine delivery technologies at the Seattle, Washington-based nonprofit Program for Appropriate Technology in Health, says that his organization is conducting trials of the PharmaJet injector for vaccination programs in Brazil.

“This is all about saving more lives and increasing access,” says Zehrung.

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Source : http://www.pnas.org