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Purdue p A team of researchers has created a new implantable drug-delivery system using nanowires that can be wirelessly controlled.

The nanowires respond to an electromagnetic field generated by a separate device, which can be used to control the release of a preloaded drug. The system eliminates tubes and wires required by other implantable devices that can lead to infection and other complications, said team leader Richard Borgens, Purdue University’s Mari Hulman George Professor of Applied Neuroscience and director of Purdue’s Center for Paralysis Research.

“This tool allows us to apply drugs as needed directly to the site of injury, which could have broad medical applications,” Borgens said. “The technology is in the early stages of testing, but it is our hope that this could one day be used to deliver drugs directly to spinal cord injuries, ulcerations, deep bone injuries or tumors, and avoid the terrible side effects of systemic treatment with steroids or chemotherapy.”

The team tested the drug-delivery system in mice with compression injuries to their spinal cords and administered the corticosteroid dexamethasone. The study measured a molecular marker of inflammation and scar formation in the central nervous system and found that it was reduced after one week of treatment. A paper detailing the results will be published in an upcoming issue of the Journal of Controlled Release and is currently available online.

Purdue U Nano Wire 94283_web

IMAGE: An image of a field of polypyrrole nanowires captured by a scanning electron microscope is shown. A team of Purdue University researchers developed a new implantable drug-delivery system using the… view more

Credit: (Purdue University image/courtesy of Richard Borgens)

The nanowires are made of polypyrrole, a conductive polymer material that responds to electromagnetic fields. Wen Gao, a postdoctoral researcher in the Center for Paralysis Research who worked on the project with Borgens, grew the nanowires vertically over a thin gold base, like tiny fibers making up a piece of shag carpet hundreds of times smaller than a human cell. The nanowires can be loaded with a drug and, when the correct electromagnetic field is applied, the nanowires release small amounts of the payload. This process can be started and stopped at will, like flipping a switch, by using the corresponding electromagnetic field stimulating device, Borgens said.

The researchers captured and transported a patch of the nanowire carpet on water droplets that were used used to deliver it to the site of injury. The nanowire patches adhere to the site of injury through surface tension, Gao said.

The magnitude and wave form of the electromagnetic field must be tuned to obtain the optimum release of the drug, and the precise mechanisms that release the drug are not yet well understood, she said. The team is investigating the release process.

The electromagnetic field is likely affecting the interaction between the nanomaterial and the drug molecules, Borgens said.

“We think it is a combination of charge effects and the shape change of the polymer that allows it to store and release drugs,” he said. “It is a reversible process. Once the electromagnetic field is removed, the polymer snaps back to the initial architecture and retains the remaining drug molecules.”

For each different drug the team would need to find the corresponding optimal electromagnetic field for its release, Gao said.

This study builds on previous work by Borgens and Gao. Gao first had to figure out how to grow polypyrrole in a long vertical architecture, which allows it to hold larger amounts of a drug and extends the potential treatment period. The team then demonstrated it could be manipulated to release dexamethasone on demand. A paper detailing the work, titled “Action at a Distance: Functional Drug Delivery Using Electromagnetic-Field-Responsive Polypyrrole Nanowires,” was published in the journal Langmuir.

Other team members involved in the research include John Cirillo, who designed and constructed the electromagnetic field stimulating system; Youngnam Cho, a former faculty member at Purdue’s Center for Paralysis Research; and Jianming Li, a research assistant professor at the center.

For the most recent study the team used mice that had been genetically modified such that the protein Glial Fibrillary Acidic Protein, or GFAP, is luminescent. GFAP is expressed in cells called astrocytes that gather in high numbers at central nervous system injuries. Astrocytes are a part of the inflammatory process and form a scar tissue, Borgens said.

A 1-2 millimeter patch of the nanowires doped with dexamethasone was placed onto spinal cord lesions that had been surgically exposed, Borgens said. The lesions were then closed and an electromagnetic field was applied for two hours a day for one week. By the end of the week the treated mice had a weaker GFAP signal than the control groups, which included mice that were not treated and those that received a nanowire patch but were not exposed to the electromagnetic field. In some cases, treated mice had no detectable GFAP signal.

Whether the reduction in astrocytes had any significant impact on spinal cord healing or functional outcomes was not studied. In addition, the concentration of drug maintained during treatment is not known because it is below the limits of systemic detection, Borgens said.

“This method allows a very, very small dose of a drug to effectively serve as a big dose right where you need it,” Borgens said. “By the time the drug diffuses from the site out into the rest of the body it is in amounts that are undetectable in the usual tests to monitor the concentration of drugs in the bloodstream.”

Polypyrrole is an inert and biocompatable material, but the team is working to create a biodegradeable form that would dissolve after the treatment period ended, he said.

The team also is trying to increase the depth at which the drug delivery device will work. The current system appears to be limited to a depth in tissue of less than 3 centimeters, Gao said.


Story Source:

The above post is reprinted from materials provided by Purdue University. The original item was written by Elizabeth K. Gardner. Note: Materials may be edited for content and length.


Journal Reference:

  1. Wen Gao, Richard Ben Borgens. Remote-controlled eradication of astrogliosis in spinal cord injury via electromagnetically-induced dexamethasone release from “smart” nanowires. Journal of Controlled Release, 2015; 211: 22 DOI: 10.1016/j.jconrel.2015.05.266

NP Cancer 061015 1-nanoparticle

Many cancer patients survive treatment only to have a recurrence within a few years. Recurrences and tumor spreading are likely due to cancer stem cells that can be tough to kill with conventional cancer drugs. But now researchers have designed nanoparticles that specifically target these hardy cells to deliver a drug. The nanoparticle treatment, reported in the journal ACS Nano, worked far better than the drug alone in mice.

Anti-cancer drugs can often shrink tumors but don’t kill (CSCs). Although CSCs might only make up a small part of a tumor, their resistance to drugs allows them to persist. They can then cause a tumor to regrow or spread throughout the body. Xiaoming He and colleagues wanted to develop a nanoparticle system to overcome these cells’ defenses.

The researchers packaged the anti-cancer drug doxorubicin into nanoparticles coated with chitosan, a natural polysaccharide that can specifically target CSCs. Once in the acidic environment of the tumor, the nanoparticles degraded and released the drug. Tests on tiny, tissue-like clumps of both normal and cancer stem cells in vitro and on human breast tumors grown in mice showed the therapy successfully killed CSCs and destroyed tumors. The mice showed no obvious side effects.

Explore further: Nano packages for anti-cancer drug delivery

More information: Chitosan-Decorated Doxorubicin-Encapsulated Nanoparticle Targets and Eliminates Tumor Reinitiating Cancer Stem-like Cells ACS Nano, Article ASAP
DOI: 10.1021/nn506928p

Abstract
Tumor reinitiating cancer stem-like cells are responsible for cancer recurrence associated with conventional chemotherapy. We developed a doxorubicin-encapsulated polymeric nanoparticle surface-decorated with chitosan that can specifically target the CD44 receptors of these cells. This nanoparticle system was engineered to release the doxorubicin in acidic environments, which occurs when the nanoparticles are localized in the acidic tumor microenvironment and when they are internalized and localized in the cellular endosomes/lysosomes. This nanoparticle design strategy increases the cytotoxicity of the doxorubicin by six times in comparison to the use of free doxorubicin for eliminating CD44+ cancer stem-like cells residing in 3D mammary tumor spheroids (i.e., mammospheres). We further show these nanoparticles reduced the size of tumors in an orthotopic xenograft tumor model with no evident systemic toxicity. The development of nanoparticle system to target cancer stem-like cells with low systemic toxicity provides a new treatment arsenal for improving the survival of cancer patients.

Journal reference: ACS Nano

Drug Delivery 050815 onereallytin When you take a drug, it travels through your bloodstream, dissolving and dispersing, and eventually reaching its designated target area.

But because the blood containing the drug travels all round your body only a small percentage of the initial dose actually reaches the desired location.

For over-the-counter drugs like paracetamol or ibuprofen, with very few side-effects, this doesn’t matter too much.

But when it comes to cancer drugs, which can affect healthy cells just as much as , this process can cause big problems.

Drug Delivery 050815 onereallytin

Partly because drugs are diluted in their blood, cancer patients need to take these drugs in particularly high doses – and this can cause seriously unpleasant side effects.

But Professor Sonia Trigueros, co-director of the Oxford Martin Programme on Nanotechnology, is inching closer to developing a nano-scale drug delivery system with the aim of specifically targeting cancer cells.

Working with a team of chemists, engineers and physicists, Trigueros has embarked on an ambitious mission to tackle cancer at the ‘nano’ level – less than 100 nanometers wide. For context, this is super-tiny: a nanometre is a thousandth of a thousandth of a millimetre.

There’s still a long way to go, but Trigueros is making decent headway, and has recently tackled a major problem of working at a nano level. And at this year’s Wired Health conference – which looked at the future of health care, wellbeing and genomics – she told us about her recent progress, and her visions for the future.

At the nano level

Some of us will remember the periodic table displayed in our science classrooms which told us about the properties of each element. But working on a nano level everything changes, and elements behave completely differently.

Elements have different properties at the nano level than they do at the micro level, explained Prof Trigueros to the Wired Health 2015 audience.

This poses big problems for researchers trying to make nano-scale devices, which can be made out of a number of different materials, including gold, silver and carbon. All these materials are highly unstable at the nano level.

“After you make the nanostructures you only have minutes to a couple of days to work,” she said. They are really unstable, especially when you put them in water.”

This isn’t ideal, considering our bodies are made up mostly of water.

One (really tiny) step closer to nano-sized cancer drug delivery
Credit: Professor Sonia Trigueros

Trigueros’ recent work has focused on trying to stabilise tiny tubes made of carbon, called carbon nanotubes, which hold drugs inside the tube so they can be delivered into cancer cells.

She has now found a way of keeping them stable for more than two years and in temperatures up to 42ºC.

To do this, she wraps DNA around the structures, like a tortilla wraps around the fillings of a burrito.

While this accomplishes the goal of keeping the nanostructures stable inside the body this doesn’t do much good if the DNA can’t unwrap to deliver the drugs. But, according to Trigueros, she has shown that, once inside a cell, the DNA easily unwinds and releases its payload.

Truly targeted drug delivery

So how does it all work? How do the drugs get into the cancer cells? Trigueros’s nanotubes exploit the differences between cancer cells and – in this case, differences in the membranes that hold them together.

“Cancer cells are more permeable than normal cells so the nanotubes can get through the cell membrane. And once they are in, they unwrap and deliver drug,” explained Trigueros.

Exploiting differences in their permeability is one way to target the cancer cells, but Trigueros explains that there is more than one way to create a truly targeted drug delivery system.

“We can attach whatever we want on DNA,” she said. “So you can attach a protein that recognises cancer cells”.

From theory to reality

While this all sounds great in theory, will it actually work in reality?

One (really tiny) step closer to nano-sized cancer drug delivery
Attaching proteins to DNA could create a truly targeted drug delivery system. Credit: Professor Sonia Trigueros

Trigueros has now started preliminary tests on laboratory grown , she told us during an interview. And this has shown tentative promise, she says, citing unpublished data on their effectiveness at killing these cells in the lab.

Others are cautiously optimistic. “This is a really exciting prospect,” says Professor Duncan Graham, nanotechnology expert and advisor to Cancer Research UK.

“A common concern with carbon nanotubes is toxicity, but when coated with DNA this concern could be removed,” he explains, “and it also addresses a fundamental issue, which is that they collect into clusters that become a solid mass and so are unable to leave the body.”

In theory, once Trigueros’s nanotubes have finished their job they are tiny enough (50 nanometres) to be excreted through urine.

This isn’t the first time carbon nanotubes have been used in cancer research: a US research team has used them, for example, to target and collect images of tumours in mice. But the combination of drug delivery and cancer-specific targeting is what interests Professor Graham.

“Unlike previous work using carbon nanotubes, this approach is set to target the tumour specifically, potentially meaning fewer side effects and a lower dosage. I look forward to seeing this in animal models which is where the real proof of activity lies,” he said.

But he’s cautious, stressing that Trigueros’s work has not yet been peer-reviewed and published.

Next steps

Next Trigueros is aiming towards starting animal trials and, eventually, she wants to begin clinical trials in patients – that is if everything goes well.

She hopes to focus on how nanostructures could be used to cross the blood-brain barrier – the brain’s highly selective ‘bouncer’ that only lets certain molecules across. This has been notoriously difficult to get past, making targeting cancers in the brain more difficult.

But there is a still a long way to go and a lot of problems to tackle. In the shorter term, we’ll be keeping an eager eye on her research, as her ideas continue to develop.

Explore further: Nano packages for anti-cancer drug delivery


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