Reading cancer’s chemical clues A nanoparticle-assisted optical imaging technique could one day read the chemical makeup of a tumor.

 

A tumor’s chemical makeup holds valuable clues about how to fight it. But today, it’s difficult or impossible to examine the chemistry inside a tumor. A nanoparticle-assisted optical imaging technique could one day enable doctors to read those clues in real time, providing a non-invasive precision medicine approach that could match treatment to individual tumors.

“Tumors vary widely from one patient to the next, so the more we know about them, the more effective our treatments become. This is especially important with chemotherapy because of its high cost and severe side effects,” said Xueding Wang, a University of Michigan professor of biomedical engineering who helped develop the technique. “This could form the basis of precision medicine treatments that offer better outcomes, fewer side effects and lower costs.”

Most of us are working in the dark with regard to tumor imaging. -Xueding Wang

Doctors already know, for example, that some treatments don’t work on acidic tumors while others are ineffective against tumors that have low oxygen levels. If they know the chemical makeup of a given tumor, they can start the right treatment immediately, then keep close tabs on its effectiveness over time.

In a recent paper, U-M researchers successfully used the process to get a three-dimensional view of the pH level inside tumors in mice, and they believe that they will also be able to use it to read a variety of other important chemical markers inside cancers. The new technology is detailed in a paper published September 7 in Nature Communication.

Images of a mouse tumor obtained with the new technique. Row A shows the presence of the nanoparticle itself, in blue. Row B shows the pH of the tumor. Image C shows oxygen saturation and image D shows hemoglobin concentration. Photo courtesy of Janggun Jo, Michigan Engineering

“Most of us are working in the dark with regard to tumor imaging. There are very few cases where we can study the chemistry of a tumor,” said Wang. ”We hope to change that with this technology, which offers a spatially detailed, real-time look at the chemistry inside a tumor, even when it’s deep inside the body.”

The technique uses a two-part system, starting with a purpose-built, injectable nanoparticle that’s absorbed only by cancerous cells. The particles were loaded with a marker dye that changes color in response to the tumor’s pH to measure acidity.

Wang and Raoul Kopelman, the Richard Smalley Distinguished University Professor of Chemistry, Physics and Applied Physics, made the nanoparticles small enough to fit through tiny cracks in the walls of cancer cells called fenestrations—imperfections that form because cancer cells grow so quickly. They then coated the particles with protein fragments, or peptides, that are attracted to cancerous cells.

“The peptides on the particle are like tugboats guiding an ocean liner,” Kopelman explained.

The particles were injected into mice, where they infiltrated the cancerous cells and the pH-sensitive dye did its work. Next, the team read the dye by flashing pulses of laser light into the tumor from outside the mouse’s body and recording the ultrasound signal that’s reflected back.

Chang Lee, Ph.D., examines the pH-sensitive dye used in the new cancer imaging technique. Photo: Akhil Kantipuly, Michigan Engineering

“Inside the body, the laser’s energy turns from light into heat, then from heat into sound, a bit like thunder,” said Wang. “We can use ultrasound to read that sound energy, then digitally convert it back to optical information. That provides a painless, non-invasive way for us to see the color change in the injected dye, even when it’s deep inside the body.”

The researchers caution that an approved treatment is several years off. But they note that the imaging technology is already under clinical trial, as are the individual components of the nanoparticle. In the meantime, they are working on similar approaches that could be used to measure markers other than pH, like potassium and oxygen levels. They envision a treatment that could measure several different aspects of a tumor’s chemistry using a single scan.

The paper is titled “In vivo quantitative imaging of tumor pH by nanosonophore assisted multi-spectral photoacoustic imaging.” The research was supported by funding from the National Institutes of Health through the National Cancer Institute (grant number R01CA186769).

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The sweet smell of science: A failed candy recipe solves a sticky problem in the lab

By Gabe Cherry
Michigan Engineering

Anyone who has made Jello knows how difficult it can be to spring the wobbly treat from its mold intact. Now, imagine trying to dislodge something 10 times softer than gelatin, while keeping every detail unscathed down to a microscopic level. That was the problem faced by University of Michigan postdoctoral researcher Chris Moraes.

Moraes’s team, led by biomedical engineering professor Shu Takayama, was studying  how scar tissue forms inside the body, specifically in the soft-celled lungs and liver. To do that, they were working with a type of silicone called Sylgard 527. It’s so soft that just a few cells can squeeze it out of shape.

“Soft silicone structures are useful for studying human cells outside the body,” Takayama said. “We can use them to measure the very small squeezing effect that cells generate during wound healing. This enables us to test the effects of drugs using very small samples of human cells, instead of testing on actual patients.”

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Moraes wanted to mold the Sylgard into tiny pillars less than a millimeter wide, then position the cells around them in a donut shape. He could then apply different treatments to the cells and measure how much their expansion and contraction squeezed the pillars out of shape.

Molding those pillars, however, turned out not to be so simple. The team was using hard epoxy molds, and there was no way to remove the silicone pillars without turning them into useless lumps of goo.

The solution came when Moraes was at home in his kitchen. An avid cook, he was trying a new recipe for homemade cotton candy.

“The cotton candy was a total failure,” he said. “I ended up with nothing but a huge blob of sugar syrup. I gave up and left it to cool in the pan.”

But when he took the hardened mass out of the pan, he noticed something surprising: The sugar retained every detail of the pan it came out of. It got him thinking: why not use hardened sugar as a mold for super-soft silicone? They could pour in the silicone, wait for it to cure, then dissolve the mold in water, leaving perfectly cast pillars of soft silicone.

The next day, Moraes was in the lab, perfecting a recipe for sacrificial sugar molds. The recipe was simple: sugar, water and corn syrup, cooked in the microwave to just the right consistency.

“It smelled great,” said biomedical engineering doctoral student Joe Labuz, who also works on the project. “The trick is to caramelize the sugar, hardening it enough so that it doesn’t deform as the silicone cures. Eventually, we got it just right and also drew a crowd of our colleagues who wondered where the great smell was coming from.”

The sugar molds turn out perfect soft silicone pillars every time.

Joseph Labuz, BME PhD Student, puts sugar molds in a water bath for the casting of soft silicone pillars in the NCRC. Photo by: Joseph Xu

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Joseph Labuz, BME PhD Student, puts sugar molds in a water bath for the casting of soft silicone pillars in the NCRC. Photo by: Joseph Xu

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The pillar-making process begins with a hard epoxy “negative mold” – a mirror image of the sugar mold used to cast the final pillars. The researchers pour in hard silicone to create an initial plastic mold. Next, the molten sugar mixture is poured into this initial plastic mold and left to cool, hardening into what looks a lot like a piece of hard candy. The hardened sugar is popped out of the initial plastic mold and the sugar is then used as a mold for the silicone. The researchers pour the silicone into the sugar mold and cure the concoction in an oven. Finally, the silicone and sugar mold are put into a water bath. The sugar dissolves, while the water-repellent silicone stays intact.

The team is using the new process to better understand how scar tissue forms inside the body. Internal scarring is a common occurrence in diseases like cancer and diabetes, where the body tries to repair organ damage done by the disease. The formation of scar tissue can cause further problems by preventing organs from working properly.

“Scarring happens when the body’s healing process goes too far,” Takayama said. “If we can prevent it from happening or even reverse it, we could reduce the impact of a lot of diseases and create better outcomes for patients.”

The candy molding process is detailed in a paper published in the journal Lab on a Chip. Labuz says it can also be used other researchers to create virtually any type of soft silicone structure. In the meantime, they’re in the lab enjoying the sweet smell of science.

The paper is titled “Supersoft lithography: candy-based fabrication of soft silicone microstructures.” The work was supported by the National Science Foundation, National Institute of Health (grant numbers CA 170198 and AI116482) and the Natural Sciences and Engineering Research Council of Canada.