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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


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