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MIT professor Paula Hammond (right) and Bryan Hsu PhD’ 14 have developed a nanoscale film that can be used to deliver medication, either directly through injections, or by coating implantable medical devices. Photo: Dominick Reuter

Nanoscale, biodegradable drug-delivery method could provide a year or more of steady doses.

About one in four older adults suffers from chronic pain. Many of those people take medication, usually as pills. But this is not an ideal way of treating pain: Patients must take medicine frequently, and can suffer side effects, since the contents of pills spread through the bloodstream to the whole body.

Now researchers at MIT have refined a technique that could enable pain medication and other drugs to be released directly to specific parts of the body — and in steady doses over a period of up to 14 months.  The method uses biodegradable, nanoscale “thin films” laden with drug molecules that are absorbed into the body in an incremental process.

“It’s been hard to develop something that releases [medication] for more than a couple of months,” says Paula Hammond, the David H. Koch Professor in Engineering at MIT, and a co-author of a new paper on the advance. “Now we’re looking at a way of creating an extremely thin film or coating that’s very dense with a drug, and yet releases at a constant rate for very long time periods.”

In the paper, published today in the Proceedings of the National Academy of Sciences, the researchers describe the method used in the new drug-delivery system, which significantly exceeds the release duration achieved by most commercial controlled-release biodegradable films.

“You can potentially implant it and release the drug for more than a year without having to go in and do anything about it,” says Bryan Hsu PhD ’14, who helped develop the project as a doctoral student in Hammond’s lab. “You don’t have to go recover it. Normally to get long-term drug release, you need a reservoir or device, something that can hold back the drug. And it’s typically nondegradable. It will release slowly, but it will either sit there and you have this foreign object retained in the body, or you have to go recover it.”

Layer by layer

The paper was co-authored by Hsu, Myoung-Hwan Park of Shamyook University in South Korea, Samantha Hagerman ’14, and Hammond, whose lab is in the Koch Institute for Integrative Cancer Research at MIT.

The research project tackles a difficult problem in localized drug delivery: Any biodegradable mechanism intended to release a drug over a long time period must be sturdy enough to limit hydrolysis, a process by which the body’s water breaks down the bonds in a drug molecule. If too much hydrolysis occurs too quickly, the drug will not remain intact for long periods in the body. Yet the drug-release mechanism needs to be designed such that a drug molecule does, in fact, decompose in steady increments.

To address this, the researchers developed what they call a “layer-by-layer” technique, in which drug molecules are effectively attached to layers of thin-film coating. In this specific case, the researchers used diclofenac, a nonsteroidal anti-inflammatory drug that is often prescribed for osteoarthritis and other pain or inflammatory conditions. They then bound it to thin layers of poly-L-glutamatic acid, which consists of an amino acid the body reabsorbs, and two other organic compounds. The film can be applied onto degradable nanoparticles for injection into local sites or used to coat permanent devices, such as orthopedic implants.

In tests, the research team found that the diclofenac was steadily released over 14 months. Because the effectiveness of pain medication is subjective, they evaluated the efficacy of the method by seeing how well the diclofenac blocked the activity of cyclooxygenase (COX), an enzyme central to inflammation in the body.

“We found that it remains active after being released,” Hsu says, meaning that the new method does not damage the efficacy of the drug. Or, as the paper notes, the layer-by-layer method produced “substantial COX inhibition at a similar level” to pills.

The method also allows the researchers to adjust the quantity of the drug being delivered, essentially by adding more layers of the ultrathin coating.

A viable strategy for many drugs

Hammond and Hsu note that the technique could be used for other kinds of medication; an illness such as tuberculosis, for instance, requires at least six months of drug therapy.

“It’s not only viable for diclofenac,” Hsu says. “This strategy can be applied to a number of drugs.”

Indeed, other researchers who have looked at the paper say the potential medical versatility of the thin-film technique is of considerable interest.

“I find it really intriguing because it’s broadly applicable to a lot of systems,” says Kathryn Uhrich, a professor in the Department of Chemistry and Chemical Biology at Rutgers University, adding that the research is “really a nice piece of work.”

To be sure, in each case, researchers will have to figure out how best to bind the drug molecule in question to a biodegradable thin-film coating. The next steps for the researchers include studies to optimize these properties in different bodily environments and more tests, perhaps with medications for both chronic pain and inflammation.

A major motivation for the work, Hammond notes, is “the whole idea that we might be able to design something using these kinds of approaches that could create an [easier] lifestyle” for people with chronic pain and inflammation.

Hsu and Hammond were involved in all aspects of the project and wrote the paper, while Hagerman and Park helped perform the research, and Park helped analyze the data.

The research described in the paper was supported by funding from the U.S. Army and the U.S. Air Force.

PEG-PDI, which incorporates a compound long used as a red dye, changes to greenish-blue with the addition of potassium superoxide as it converts the superoxide to dioxygen. Adding more further quenches the reactive oxygen species superoxide, turning the solution purple. Adding hydrogen peroxide in the last step clarifies the liquid, showing that a build-up of excess hydrogen peroxide can deactivate the structure. PEG-PDI, created at Rice University, shows potential as a biological antioxidant. Credit: Tour Group/Rice University

Treated particles of graphene derived from carbon nanotubes have demonstrated remarkable potential as life-saving antioxidants, but as small as they are, something even smaller had to be created to figure out why they work so well.

 

Researchers at Rice University, the McGovern Medical School at the University of Texas Health Science Center at Houston (UTHealth) and Baylor College of Medicine created single-molecule compounds that also quench damaging reactive oxygen species (ROS) but are far easier to analyze using standard scientific tools. The molecules may become the basis for new antioxidant therapies in their own right.

The research appears in the American Chemical Society journal ACS Nano.

The original compounds are hydrophilic carbon clusters functionalized with polyethylene glycol, known as PEG-HCCs and created by Rice and Baylor scientists five years ago. The particles help neutralize ROS molecules overexpressed by the body’s cells in response to an injury before they damage cells or cause mutations.

PEG-HCCs show promise for treating cancer, rebooting blood flow in the brain after traumatic injury and controlling chronic diseases.

The new particles, called PEG-PDI, consist of polyethylene glycol and perylene diimide, a compound used as a dye, the color in red car paint and in solar cells for its light-absorbing properties. Their ability to accept electrons from other molecules makes them functionally similar to PEG-HCCs.

They’re close enough to serve as an analog for experiments, according to Rice chemist James Tour, who led the study with University of Texas biochemist Ah-Lim Tsai.

The researchers wrote that the molecule is not only the first example of a small molecular analogue of PEG-HCCs, but also represents the first successful isolation of a PDI radical anion as a single crystal, which allows its structure to be captured with X-ray crystallography.

“This allows us to see the structure of these active particles,” Tour said. “We can get a view of every atom and the distances between them, and get a lot of information about how these molecules quench destructive oxidants in biological tissue.

“Lots of people get crystal structures for stable compounds, but this is a transient intermediate during a catalytic reaction,” he said. “To be able to crystallize a reactive intermediate like that is amazing.”

Antioxidant compounds mimic effective graphene agents, show potential for therapies 



The crystal structure of PEG-PDI is achieved using cobaltocene as a reducing agent and omitting solvents and hydrogen atoms for clarity. Carbon atoms are gray, nitrogens are blue, oxygens red and cobalts purple. The molecules created by scientists at Rice University, the McGovern Medical School at the University of Texas Health Science Center at Houston and Baylor College of Medicine are efficient antioxidants and help scientists understand how larger nanoparticles quench damaging reactive oxygen species in the body. Credit: Tour Group

PEG-HCCs are about 3 nanometers wide and 30 to 40 nanometers long. By comparison, much simpler PEG-PDI molecules are less than a nanometer in width and length.

 

PEG-PDI molecules are true mimics of superoxide dismutase enzymes, protective antioxidants that break down toxic superoxide radicals into harmless molecular oxygen and hydrogen peroxide. The molecules pull electrons from unstable ROS and catalyze their transformation into less-reactive species.

Testing the PEG-PDI molecules can be as simple as putting them in a solution that contains reactive oxygen species molecules like potassium superoxide and watching the solution change color. Further characterization with electron paramagnetic resonance spectroscopy was more complicated, but the fact that it’s even possible makes them powerful tools in resolving mechanistic details, the researchers said.

Tour said adding polyethylene glycol makes the molecules soluble and also increases the amount of time they remain in the bloodstream. “Without PEG, they just go right out of the system through the kidneys,” he said.

When the PEG groups are added, the molecules circulate longer and continue to catalyze reactions.

He said PEG-PDI is just as effective as PEG-HCCs if measured by weight. “Because they have so much more surface area, PEG-HCC particles probably catalyze more parallel reactions per particle,” Tour said. “But if you compare them with PEG-PDI by weight, they are quite similar in total catalytic activity.”

Understanding the structure of PEG-PDI should allow researchers to customize the molecule for applications. “We should have a tremendous ability to modify the molecule’s structure,” he said. “We can add anything we want, exactly where we want, for specific therapies.”

The researchers said PEG-PDI may also be efficient metal- and protein-free catalysts for oxygen reduction reactions used in industry and essential to fuel cells. They are intrinsically more stable than enzymes and can function in much a wider pH range, Tsai said.

Co-author Thomas Kent, a professor of neurology at Baylor who has worked on the project from the start, noted small molecules have a better chance to get on the fast track to approval for therapy by the Food and Drug Administration than nanotube-based agents.
“A small molecule that is not derived from larger nanomaterial may have a better chance of approval to use in humans, assuming it is safe and effective,” he said.

Tour said PEG-PDI serves as a precise model for other graphene derivatives like graphene oxide and permits a more detailed study of graphene-based nanomaterials.

“Making nanomaterials smaller, from well-defined molecules, permits 150 years of synthetic chemistry methods to address the mechanistic questions within nanotechnology,” he said.

 

More information: Almaz S. Jalilov et al. Perylene Diimide as a Precise Graphene-Like Superoxide Dismutase Mimetic, ACS Nano (2017). DOI: 10.1021/acsnano.6b08211

Provided by: Rice University

Cancer shapeshiftin
Professor Warren Chan (IBBME, ChemE, MSE) has spent the last decade figuring out how to deliver chemotherapy drugs into tumours — and nowhere else. Now his lab has designed a set of nanoparticles attached to strands of DNA that can change …more

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

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

Professor Warren Chan (IBBME, ChemE, MSE) has spent the last decade figuring out how to deliver into tumours—and nowhere else. Now his lab has designed a set of nanoparticles attached to strands of DNA that can change shape to gain access to diseased tissue.

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

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

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

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

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

Their work was published this week in two key studies in the Proceedings of the National Academy of Sciences and the leading journal Science.

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

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

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

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

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

Explore further: Cylindrical nanoparticles more deadly to breast cancer

More information: Edward A. Sykes et al. Tailoring nanoparticle designs to target cancer based on tumor pathophysiology, Proceedings of the National Academy of Sciences(2016). DOI: 10.1073/pnas.1521265113

Cancer Nanoparticle Targets 160210165715_1_540x360In one of the first efforts to date to apply nanotechnology to targeted cancer therapeutics, researchers have created a nanoparticle formulation of a cancer drug that is both effective and nontoxic — qualities harder to achieve with the free drug. Their nanoparticle creation releases the potent but toxic targeted cancer drug directly to tumors, while sparing healthy tissue.

The findings in rodents with human tumors have helped launch clinical trials of the nanoparticle-encapsulated version of the drug, which are currently underway. Aurora kinase inhibitors are molecularly targeted agents that disrupt cancer’s cell cycle.

While effective, the inhibitors have proven highly toxic to patients and have stalled in late-stage trials. Development of several other targeted cancer drugs has been abandoned because of unacceptable toxicity. To improve drug safety and efficacy, Susan Ashton and colleagues designed polymeric nanoparticles called Accurins to deliver an Aurora kinase B inhibitor currently in clinical trials.

The nanoparticle formulation used ion pairing to efficiently encapsulate and control the release of the drug. In colorectal tumor-bearing rats and mice with diffuse large B cell lymphoma, the nanoparticles accumulated specifically in tumors, where they slowly released the drug to cancer cells. Compared to the free drug, the nanoparticle-encapsulated inhibitor blocked tumor growth more effectively at one half the drug dose and caused fewer side effects in the rodents.

Cancer Nanoparticle Targets 160210165715_1_540x360

The polymeric nanoparticle Accurin encapsulates the clinical candidate AZD2811, an Aurora B kinase inhibitor. This material relates to a paper that appeared in the Feb. 10, 2016 issue of Science Translational Medicine, published by AAAS. The paper, by S. Ashton at institution in location, and colleagues was titled, “Aurora kinase inhibitor nanoparticles target tumors with favorable therapeutic index in vivo.”
Credit: Ashton et al., Science Translational Medicine (2016)

A related Focus by David Bearss offers more insights on how Accurin nanoparticles may help enhance the safety and antitumor activity of Aurora kinase inhibitors and other molecularly targeted drugs.


Story Source:

The above post is reprinted from materials provided by American Association for the Advancement of Science. Note: Materials may be edited for content and length.


Journal Reference:

  1. Susan Ashton, Young Ho Song, Jim Nolan, Elaine Cadogan, Jim Murray, Rajesh Odedra, John Foster, Peter A. Hall, Susan Low, Paula Taylor, Rebecca Ellston, Urszula M. Polanska, Joanne Wilson, Colin Howes, Aaron Smith, Richard J. A. Goodwin, John G. Swales, Nicole Strittmatter, Zoltán Takáts, Anna Nilsson, Per Andren, Dawn Trueman, Mike Walker, Corinne L. Reimer, Greg Troiano, Donald Parsons, David De Witt, Marianne Ashford, Jeff Hrkach, Stephen Zale, Philip J. Jewsbury, and Simon T. Barry. Aurora kinase inhibitor nanoparticles target tumors with favorable therapeutic index in vivo. Science Translational Medicine, 2016 DOI: 10.1126/scitranslmed.aad2355

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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