Findings in mice show pill for breast cancer diagnosis may outperform mammograms A new kind of imaging could distinguish aggressive tumors from benign, preventing unnecessary breast cancer treatments.

As many as one in three women treated for breast cancer undergo unnecessary procedures, but a new method for diagnosing it could do a better job distinguishing between benign and aggressive tumors. Researchers at the University of Michigan are developing a pill that makes tumors light up when exposed to infrared light, and they have demonstrated that the concept works in mice.

Mammography is an imprecise tool. About a third of breast cancer patients treated with surgery or chemotherapy have tumors that are benign or so slow-growing that they would never have become life-threatening, according to a study out of Denmark last year. In other women, dense breast tissue hides the presence of lumps and results in deaths from treatable cancers. All that, and mammograms are notoriously uncomfortable.

“We overspend $4 billion per year on the diagnosis and treatment of cancers that women would never die from,” said Greg Thurber, an assistant professor of chemical engineering and biomedical engineering, who led the team. “If we go to molecular imaging, we can see which tumors need to be treated.”

The move could also catch cancers that would have gone undetected. Thurber’s team uses a dye that responds to infrared light to tag a molecule commonly found on tumor cells, in the blood vessels that feed tumors and in inflamed tissue. By providing specific information on the types of molecules on the surface of the tumor cells, physicians can better distinguish a malignant cancer from a benign tumor.

Compared to visible light, infrared light penetrates the body easily—it can get to all depths of the breast without an X-ray’s tiny risk of disrupting DNA and seeding a new tumor. Using a dye delivered orally rather than directly into a vein also improves the safety of screening, as a few patients in 10,000 can have severe reactions to intravenous dyes. These small risks turn out to be significant when tens of millions of women are screened every year in the US alone.

But it’s not easy to design a pill that can carry the dye to the tumor.

“To get a molecule absorbed into the bloodstream, it needs to be small and greasy. But an imaging agent needs to be larger and water-soluble. So you need exact opposite properties,” said Thurber.

Fortunately, they weren’t the only people looking for a molecule that could get from the digestive system to a tumor. The pharmaceutical company Merck was working on a new treatment for cancer and related diseases. They got as far as phase II clinical trials demonstrating its safety, but unfortunately, it wasn’t effective.

“It’s actually based on a failed drug,” said Thurber. “It binds to the target, but it doesn’t do anything, which makes it perfect for imaging.”

The targeting molecule has already been shown to make it through the stomach unscathed, and the liver also gives it a pass, so it can travel through the bloodstream. The team attached a molecule that fluoresces when it is struck with infrared light to this drug. Then, they gave the drug to mice that had breast cancer, and they saw the tumors light up.

“It’s actually based on a failed drug. It binds to the target, but it doesn’t do anything, which makes it perfect for imaging.”Greg Thurber

The research is described in a paper in the journal Molecular Pharmaceutics, titled, “Oral administration and detection of a near-infrared molecular imaging agent in an orthotopic mouse model for breast cancer screening.”

This work was done in collaboration with David Smith, the John G. Wagner Collegiate Professor of Pharmaceutical Sciences in the College of Pharmacy, and a member of the Comprehensive Cancer Center.

The study was supported by the Foundation for Studying and Combating Cancer and the National Institutes of Health.

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Bionic heart tissue: U-Michigan part of $20M center Scar tissue left over from heart attacks creates dead zones that don’t beat. Bioengineered patches could fix that.

The University of Michigan is partnering on an ambitious $20 million project to grow new heart tissue for cardiac patients. The new research center has been awarded to Boston University (BU), with strong partnership from U-M and Florida International University (FIU).

“A heart attack creates scar tissue, and the heart never returns to full function. But for every person, we could create a living patch that a surgeon could stitch in,” said Stephen Forrest, who leads the nanotechnology aspect of the project and is U-M’s Peter A. Franken Distinguished University Professor of Engineering. “It’s very audacious.”

The project is a National Science Foundation Engineering Research Center. These 5-year grants are typically renewed for another 5 years, so the researchers are looking at a 10-year timeline to go from the current state of tissue engineering to working, implantable heart tissue.

A heart attack creates scar tissue, but we could create a living patch that a surgeon could stitch in.Steve Forrest

“Heart disease is one of the biggest problems we face,” said David Bishop, director of the new center and a BU professor of electrical and computer engineering and physics. “This grant gives us the opportunity to define a societal problem, and then create the industry to solve it.”

The living patches the researchers are developing would consist of heart muscle cells, blood vessels to carry nutrients in and waste out, and optical circuitry to make the heart muscle cells beat in synchrony. Already, researchers in the lab have been developing ways to structure cells in scaffolds that mimic particular organs and grow blood vessels into artificial tissues. But typically, working implants have been static, biodegradable materials such as artificial windpipes that the body gradually replaces with tissue. Working tissue, like heart muscle, would need to be responsive as soon as it was implanted.

Engineering Research Center grants are extremely competitive, with only four of more than 200 applicants receiving an award in 2017. These centers are designed to work directly with industry to translate breakthroughs along the way out of the lab and into healthcare. Just producing a more true-to-life “heart on a chip” could aid the pharmaceutical industry in developing better treatments for problems such as arrhythmia.

Ramcharan and her colleagues in Lahann’s lab will help design and produce a polymer-protein construct that mimics the 3D matrix connecting the cells in human heart muscle. Heart muscle cells moving into this environment will then be able to link up into a single tissue. Photo: Joseph Xu, Michigan Engineering Communications & Marketing.

In order to produce the heart tissue, the team intends to start with an artificial scaffold that mimics the 3D structure of heart tissue. Joerg Lahann, a U-M professor of chemical engineering, will work with the team building the flexible polymer scaffold, as well as on the attachment and monitoring of cells within that framework.

“Michigan is pleased to lend expertise to the development of implantable heart tissue, which could improve and extend so many lives,” said Alec D. Gallimore, the Robert J. Vlasic Dean of Engineering. “Our faculty members are leaders in nanotechnology and in developing materials that support and interact with living cells and tissues, two areas that are critical to the project’s success.”

The 3D scaffold will initially be peppered with nanometer-sized gold patches that act as attachment points for protein fragments, called peptides, which will then serve as anchors for the cells. They will be printed onto the gold patches using a technique developed by Forrest and Max Shtein, a U-M associate professor of materials science and engineering. This method, called organic vapor jet printing, was initially invented for mass-producing electronic devices.

“The adaptation of this technology to biological systems represents a radically new step,” said Forrest. U-M will receive $2.8 million for these contributions.

Christopher Chen, the center’s director of cellular engineering and a BU professor of biomedical engineering, will lead the effort to grow heart muscle cells on the scaffold and infuse the tissue with blood vessels. Meanwhile, Alice White, director of nanomechanics and chair of the BU mechanical engineering department will work closely with Arvind Agarwal, an FIU professor of mechanical and materials engineering, to produce an artificial nervous system that uses light to synchronize the heartbeat in the tissue.

Stacy Ramcharan, a doctoral student in chemical engineering, uses a computerized system to layer polymer fibers, forming a scaffold for growing cells into artificial tissues. Photo: Joseph Xu, Michigan Engineering Communications & Marketing.

“It’s humbling to have the opportunity to work on something that could really be a game changer,” says Bishop. “If we succeed, we’ll save a lot of lives and add meaningful years for many people.”

In addition to the technical thrusts led by Forrest, Chen and White, Thomas Bifano, a professor of mechanical engineering and director of BU’s Photonics Center, will direct imaging.

Along with the core partners, Harvard Medical School, Columbia University, the Wyss Institute at Harvard, Argonne National Laboratory, the École Polytechnique Fédérale de Lausanne in Switzerland, and the Centro Atómico in Argentina will offer expertise in bioengineering, nanotechnology, and other areas.

Forrest is also the Paul G. Goebel Professor of Engineering, and a professor of electrical engineering and computer science, material science and engineering, and physics. Lahann is also a professor of material science and engineering, biomedical engineering, and macromolecular science and engineering. Shtein is also an associate professor of chemical engineering, macromolecular science and engineering, and art and design. Gallimore is also the Richard F. and Eleanor A. Towner Professor, an Arthur F. Thurnau Professor, and a professor of aerospace engineering.

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