Nanotechnology infiltrates and quashes aggressive cancers that survive traditional therapy

Researchers at Case Western Reserve University have received two grants totaling nearly $1.7 million to build nanoparticles that seek and destroy metastases too small to be detected with current technologies.

They are targeting aggressive cancers that persist through traditional chemotherapy and can form new tumors. The stealthy travel and growth of micrometastases is the hallmark of metastatic disease, the cause of most cancer deaths worldwide.

The group, led by Efstathios Karathanasis, assistant professor of biomedical engineering and radiology, will spend the next five years perfecting molecular coatings, called ligands, that enable nanochains injected into a patient's blood to home in on micrometastases. The National Cancer Institute awarded the group $1.6 million to pursue the work.

The Ohio Cancer Research Associates awarded the group another $60,000 to increase the efficiency and rapid dispersal of chemotherapy drugs the nanochains tote inside the metastases.

The grants will build on earlier work by Karathanasis, Mark Griswold, professor of radiology and director of MRI research at the Case Western Reserve School of Medicine, and Ruth Keri, professor of pharmacology at the Case Western Reserve School of Medicine and associate director of research at the Case Comprehensive Cancer Center. They and colleagues invented a nanochain that explodes a barrage of chemotherapy drugs inside a tumor.

"When a patient is diagnosed with cancer, he or she undergoes surgery to remove the primary tumor, then undergoes chemotherapy to kill any residual disease, including distant micrometastases," Karathanasis said.

"Chemotherapy drugs are very potent, but because they are randomly dispersed throughout the body in traditional chemotherapy, they aren't effective with the aggressive forms of cancer," he continued. "You have to give the patient so much of the drug that it would kill the patient before killing those micrometastases."

But delivering the killer drug only to micrometastases is a challenge. They are hidden among healthy cells in such small numbers they don't make a blip on today's imaging screens.

Contrary to traditional drugs, you can control how a nanoparticle travels in the bloodstream by changing its size and shape. "You can think of nanoparticles as a pile of leaves in the back yard," Karathanasis said. "When the wind blows, each leaf has a different trajectory because each has a different weight, size and shape. As engineers, we study how nanoparticles flow inside the body."

The group built a nanochain with a tail made of magnetized iron oxide links and a balloon-like sphere filled with a chemotherapy drug. The chains are designed to tumble out of the main flow in blood vessels, travel along the walls and latch onto integrins, the glue that binds newly forming micrometastasis onto the vessel wall.

When chains congregate inside tumors, researchers place a wire coil, called a solenoid, outside the animal models. Electricity passed through the solenoid creates a radiofrequency field, which causes the magnetic tails on the chains to vibrate, breaking open the chemical-carrying spheres and launching the chemotherapeutic drug deep into a metastasis.

In testing a mouse model of breast cancer metastasis, the chains killed 3000 times the number of cancerous cells as traditional chemotherapy, extended life longer and in some cases completely eradicated the disease, while limiting damage to healthy tissue.

Due to their random dispersal, negligible amounts of a typical conventional chemo drug can reach into a metastasis. In recent testing, a remarkable 6 percent of the nanochains injected in a mouse model congregated within a micrometastatic site of only a millimeter in size. The researchers want even better.

Using the federal grant, the researchers will develop nanochains with at least two ligands, which are molecular coatings designed to draw and link the chains to micrometastases.

The different ligands will seek different locations on cancerous cells, increasing the odds of finding and attacking the target.

Using the Ohio grant, the researchers will find the optimal size of the nanochains, tail and the payload of drugs to make them as efficient and speedy killers as possible. By including fluorescent materials in the nanochains, they will be able to see the chains slip from the blood stream, congregate in micrometastases and explode the drugs inside, and make improvements from there.

Other members of the research group include Vikas Gulani, assistant professor of radiology at Case Western Reserve School of Medicine and director of MRI at UH Case Medical Center, Chris Flask, director of the Imaging Core Center in the Case Comprehensive Cancer Center and an assistant professor of radiology, and William Schiemann, an associate professor at the Case Comprehensive Cancer Center.

"Such work would not happen in other places", Karathanasis said. "This is truly interactive research with my lab, the Laboratory for Nanomedical Engineering, the Case Center for Imaging Research and the Case Comprehensive Cancer Center."