A new sensor to help determine cancer therapy

Illustration of a cancer cell.

Hydrogen peroxide-sensing molecule reveals whether chemotherapy drugs are having their intended effects.

MIT chemical engineers have developed a new sensor that lets them see inside cancer cells and determine whether the cells are responding to a particular type of chemotherapy drug.

The sensors, which detect hydrogen peroxide inside human cells, could help researchers identify new cancer drugs that boost levels of hydrogen peroxide, which induces programmed cell death. The sensors could also be adapted to screen individual patients’ tumors to predict whether such drugs would be effective against them.

“The same therapy isn’t going to work against all tumors,” says Hadley Sikes, an associate professor of chemical engineering at MIT. “Currently there’s a real dearth of quantitative, chemically specific tools to be able to measure the changes that occur in tumor cells versus normal cells in response to drug treatment.”

Sikes is the senior author of the study, which appears in the Aug. 7 issue of Nature Communications. The paper’s first author is graduate student Troy Langford; other authors are former graduate students Beijing Huang and Joseph Lim and graduate student Sun Jin Moon.

Tracking hydrogen peroxide

Cancer cells often have mutations that cause their metabolism to go awry and produce abnormally high fluxes of hydrogen peroxide. When too much of the molecule is produced, it can damage cells, so cancer cells become highly dependent on antioxidant systems that remove hydrogen peroxide from cells.

Drugs that target this vulnerability, which are known as “redox drugs,” can work by either disabling the antioxidant systems or further boosting production of hydrogen peroxide. Many such drugs have entered clinical trials, with mixed results.

“One of the problems is that the clinical trials usually find that they work for some patients and they don’t work for other patients,” Sikes says. “We really need tools to be able to do more well-designed trials where we figure out which patients are going to respond to this approach and which aren’t, so more of these drugs can be approved.”

To help move toward that goal, Sikes set out to design a sensor that could sensitively detect hydrogen peroxide inside human cells, allowing scientists to measure a cell’s response to such drugs.

Existing hydrogen peroxide sensors are based on proteins called transcription factors, taken from microbes and engineered to fluoresce when they react with hydrogen peroxide. Sikes and her colleagues tried to use these in human cells but found that they were not sensitive in the range of hydrogen peroxide they were trying to detect, which led them to seek human proteins that could perform the task.

Through studies of the network of human proteins that become oxidized with increasing hydrogen peroxide, the researchers identified an enzyme called peroxiredoxin that dominates most human cells’ reactions with the molecule. One of this enzyme’s many functions is sensing changes in hydrogen peroxide levels.

Langford then modified the protein by adding two fluorescent molecules to it — a green fluorescent protein at one end and a red fluorescent protein at the other end. When the sensor reacts with hydrogen peroxide, its shape changes, bringing the two fluorescent proteins closer together. The researchers can detect whether this shift has occurred by shining green light onto the cells: If no hydrogen peroxide has been detected, the glow remains green; if hydrogen peroxide is present, the sensor glows red instead.

Predicting success

The researchers tested their new sensor in two types of human cancer cells: one set that they knew was susceptible to a redox drug called piperlongumine, and another that they knew was not susceptible. The sensor revealed that hydrogen peroxide levels were unchanged in the resistant cells but went up in the susceptible cells, as the researchers expected.

Sikes envisions two major uses for this sensor. One is to screen libraries of existing drugs, or compounds that could potentially be used as drugs, to determine if they have the desired effect of increasing hydrogen peroxide concentration in cancer cells. Another potential use is to screen patients before they receive such drugs, to see if the drugs will be successful against each patient’s tumor. Sikes is now pursuing both of these approaches.

“You have to know which cancer drugs work in this way, and then which tumors are going to respond,” she says. “Those are two separate but related problems that both need to be solved for this approach to have practical impact in the clinic.”

Learn more: Sensor could help doctors select effective cancer therapy

 

 

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Low-cost Hydrogen Peroxide Device Has the Potential to Provide Developing Countries with Clean Water

Schematic illustration of an on-site water purification system for rural communities. Powered by solar panels, the low-cost, portable device produces hydrogen peroxide from oxygen gas and water. (Zhihua Chen/Stanford University)

New Device Produces Hydrogen Peroxide for Water Purification

Limited access to clean water is a major issue for billions of people in the developing world, where water sources are often contaminated with urban, industrial and agricultural waste. Many disease-causing organisms and organic pollutants can be quickly removed from water using hydrogen peroxide without leaving any harmful residual chemicals. However, producing and distributing hydrogen peroxide is a challenge in many parts of the world.

Now scientists at the Department of Energy’s SLAC National Accelerator Laboratory and Stanford University have created a small device for hydrogen peroxide production that could be powered by renewable energy sources, like conventional solar panels.

“The idea is to develop an electrochemical cell that generates hydrogen peroxide from oxygen and water on site, and then use that hydrogen peroxide in groundwater to oxidize organic contaminants that are harmful for humans to ingest,” said Chris Hahn, a SLAC associate staff scientist.

Their results were reported March 1 in Reaction Chemistry and Engineering.

The project was a collaboration between three research groups at the SUNCAT Center for Interface Science and Catalysis, which is jointly run by SLAC and Stanford University.

“Most of the projects here at SUNCAT follow a similar path,” said Zhihua (Bill) Chen, a graduate student in the group of Tom Jaramillo, an associate professor at SLAC and Stanford. “They start from predictions based on theory, move to catalyst development and eventually produce a prototype device with a practical application.”

Teamwork

In this case, researchers in the theory group led by SLAC/Stanford Professor Jens Nørskov used computational modeling, at the atomic scale, to investigate carbon-based catalysts capable of lowering the cost and increasing the efficiency of hydrogen peroxide production. Their study revealed that most defects in these materials are naturally selective for generating hydrogen peroxide, and some are also highly active. Since defects can be naturally formed in the carbon-based materials during the growth process, the key finding was to make a material with as many defects as possible.

“My previous catalyst for this reaction used platinum, which is too expensive for decentralized water purification,” said research engineer Samira Siahrostami. “The beautiful thing about our cheaper carbon-based material is that it has a huge number of defects that are active sites for catalyzing hydrogen peroxide production.”

Stanford graduate student Shucheng Chen, who works with Stanford Professor Zhenan Bao, then prepared the carbon catalysts and measured their properties. With the help of SSRL staff scientists Dennis Nordlund and Dimosthenis Sokaras, these catalysts were also characterized using X-rays at SLAC’s Stanford Synchrotron Radiation Lightsource (SSRL), a DOE Office of Science User Facility.

“We depended on our experiments at SSRL to better understand our material’s structure and check that it had the right kinds of defects,” Shucheng Chen said.

Finally, he passed the catalyst along to his roommate Bill Chen, who designed, built and tested their device.

“Our device has three compartments,” Bill Chen explained. “In the first chamber, oxygen gas flows through the chamber, interfaces with the catalyst made by Shucheng and is reduced into hydrogen peroxide. The hydrogen peroxide then enters the middle chamber, where it is stored in a solution.” In a third chamber, another catalyst converts water into oxygen gas, and the cycle starts over.

Separating the two catalysts with a middle chamber makes the device cheaper, simpler and more robust than separating them with a standard semi-permeable membrane, which can be attacked and degraded by the hydrogen peroxide.

The device can also run on renewable energy sources available in villages. The electrochemical cell is essentially an electrical circuit that operates with a small voltage applied across it. The reaction in chamber one puts electrons into oxygen to make hydrogen peroxide, which is balanced by a counter reaction in chamber three that takes electrons from water to make oxygen — matching the current and completing the circuit. Since the device requires only about 1.7 volts applied between the catalysts, it can run on a battery or two standard solar panels.

The Future

The research groups are now working on a higher-capacity device.

Currently the middle chamber holds only about 10 microliters of hydrogen peroxide; they want to make it bigger. They’re also trying to continuously circulate the liquid in the middle chamber to rapidly pump hydrogen peroxide out, so the size of the storage chamber no longer limits production.

They would also like to make hydrogen peroxide in higher concentrations. However, only a few milligrams are needed to treat one liter of water, and the current prototype already produces a sufficient concentration, which is one-tenth the concentration of the hydrogen peroxide that you buy at the store for your basic medical needs.

In the long term, the team wants to change the alkaline environment inside the cell to a neutral one that’s more like water. This would make it easier for people to use, because the hydrogen peroxide could be mixed with drinking water directly without having to neutralize it first.

The team members are excited about their results and feel they are on the right track to developing a practical device.

“Currently it’s just a prototype, but I personally think it will shine in the area of decentralized water purification for the developing world,” said Bill Chen. “It’s like a magic box. I hope it can become a reality.”

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Research reveals mechanism for direct synthesis of hydrogen peroxide as an alternative to chlorine

Instead of reacting together on the surface of the catalyst (the palladium cluster), the hydrogen atoms dissociate into their components--protons and electrons. The protons enter the surrounding solution of water and methanol, while the electrons flow through the palladium itself into oxygen molecules. Credit: American Chemical Society.

Instead of reacting together on the surface of the catalyst (the palladium cluster), the hydrogen atoms dissociate into their components–protons and electrons. The protons enter the surrounding solution of water and methanol, while the electrons flow through the palladium itself into oxygen molecules. Credit: American Chemical Society.

From the polyurethane that makes our car seats to the paper made from bleached wood pulp, chlorine can be found in a variety of large-scale manufacturing processes. But while chlorine is good at activating the strong bonds of molecules, which allows manufacturers to synthesize the products we use on a daily basis, it can be an insidious chemical, sometimes escaping into the environment as hazardous byproducts such as chloroform and dioxin.

As a result, scientists and companies have been exploring a more environmentally benign alternative to chlorine—hydrogen peroxide, or H2O2. But it is an expensive reactant. Hydrogen peroxide is typically made in big, centralized facilities and requires significant energy for separation, concentration, and transportation. A handful of large-scale facilities around the globe have begun to produce H2O2 using the current process, but at the same facilities as the polyurethane precursors, which results in significant cost and energy savings and reduces environmental impact. Ideally smaller-scale factories would also be able to make hydrogen peroxide on site, but this would require a completely different set of chemistry, direct synthesis of H2O2 from hydrogen and oxygen gas, which has long been poorly understood according to University of Illinois researchers.

New research from David Flaherty, assistant professor of chemical and biomolecular engineering, and graduate student Neil Wilson reveals the mechanism for the direct synthesis of H2O2 on palladium cluster catalysts, and paves the way to design improved catalysts to produce H2O2 to use in place of harmful chlorine, regardless of the scale of the production facility. The research appears as the cover story for the Jan. 20, 2016 issue of the Journal of the American Chemical Society.

The commonly accepted mechanism for direct synthesis of H2O2 essentially states that hydrogen and oxygen atoms bind adjacent to one another on the catalyst surface and then react, Wilson said. To better understand what was going on, he spent over a year building a reactor, fine-tuning experimental procedures, then collecting and analyzing reaction rate data.

“What people thought was happening is after the hydrogen atoms broke apart and they’re adsorbed onto the palladium surface, that they just reacted with the oxygen on the surface. But that’s not really consistent with what we saw,” said Wilson, a fourth-year graduate student in Flaherty’s lab and first author of the article, “Mechanism for the Direct Synthesis of H2O2 on Pd Clusters: Heterolytic Reaction Pathways at the Liquid–Solid Interface.”

Featured on the journal’s cover is an image that depicts their findings: Instead of reacting together on the surface of the catalyst (the palladium cluster), the hydrogen atoms dissociate into their components—protons and electrons. The protons enter the surrounding solution of water and methanol, while the electrons flow through the palladium itself into oxygen molecules.

“When oxygen comes down onto the surface, it can react with pairs of protons and electrons to form hydrogen peroxide,” Wilson said.

“The reason this is critical,” Flaherty said, “is because it gives us guidance for how to make the next generation of these materials. This is all motivated by trying to make hydrogen peroxide more cheaply so it can be manufactured more easily, so we can use it in place of chlorine. But we didn’t know how to go about making a catalyst that was better than what we have now.”

Read more: Research reveals mechanism for direct synthesis of hydrogen peroxide