Innovators

Tiny but Mighty:
A Nanoprobe Conquers the Blood-Brain Barrier

Scorpion venom, crustacean shell, and nanoparticles: Miqin Zhang's work with these substances has produced stunning advances that one day could revolutionize treatment for intractable medical problems such as brain cancer and nerve injury.

The blood-brain barrier, long considered virtually impenetrable, has given way to the invasive prowess of a specially designed nanoparticle. This achievement is turning scientific heads, but more important, holds promise for vastly improving diagnosis and treatment of brain tumors, among the most deadly cancers.

Leading the interdisciplinary team of UW engineering and medical scientists is Miqin Zhang, professor of materials science and engineering and adjunct in radiology, neurological surgery, and orthopaedics/sports medicine.

In the team’s landmark study, fluorescent nanoprobes injected into the bloodstream of mice crossed the blood-brain barrier and attached to tumors, lighting them up. “We call it brain tumor illumination or brain tumor painting,” Zhang said.

In the brain, cancer invades the surrounding tissue, without a clear boundary between normal tissue and the tumor, which makes diagnosis and treatment more difficult. The nanoparticles increase the contrast between cancerous and normal tissue in MRI scans and in optical imaging used during surgery. They could improve imaging resolution by a factor of ten, to detect smaller tumors and enable earlier treatment.

“Precise imaging of brain tumors is phenomenally important. Patient survival is directly related to the amount of tumor that you can resect,” said Richard Ellenbogen, professor and chair of neurological surgery and research team member. “This is next-generation imaging.”

The team’s nanoprobe is an iron oxide nanoparticle coated with a biocompatible co-polymer and coupled with a tumor-targeting agent and an infrared fluorescent dye. It is a third the size of nanoparticles used elsewhere in the body.

The probe’s tumor-targeting agent is chlorotoxin, derived from scorpion venom. It binds to a surface protein produced in excess by many types of tumors. For more than a decade, researchers have been studying chlorotoxin’s ability to disrupt the spread of invasive tumors, and some centers are now conducting trials in cancer patients.

Zhang’s team decided to try using nanoparticles as the delivery system for chlorotoxin. They grew mouse-brain cancer cells in the lab and found that the chlorotoxin attached to nanoparticles decreased tumor spread by 98 percent, more than twice the decrease for chlorotoxin alone. The combined particle may inhibit the tumor cell’s ability to elongate and thus more easily invade other tissue.

“This finding was quite a surprise to us,” Zhang said. “We think this approach also might be useful in slowing the spread of cancers of the breast, colon, skin, lung, prostate, and ovaries.”

Rejoining Severed Nerves

Zhang and her team also have taken on a big problem impeding regeneration of severed peripheral nerves. At each nerve end surgeons graft on tiny tubes, called nerve guides, to channel the severed nerve fibers to grow toward each other. Commercial nerve guides made from collagen (a protein) can trigger an immune response and are prone to collapse in wet environments.

“A nerve guide needs to be biocompatible, stable in solution, resistant to collapse, and also pliable, so that surgeons can suture it to the nerve,” Zhang said.

Chitosan, found in the shells of crab and shrimp, is biodegradable and biocompatible and is FDA approved for many applications, but like collagen, it also weakens in the wet environment inside the body.

Zhang and colleagues created a new hybrid fiber of chitosan and a strong, flexible, biodegradable polyester commonly used in sutures. The nanoscale-size woven fibers combine the biological advantages of the natural material with the mechanical strength of the synthetic polymer.

“The new material would work well for wound dressings, heart grafts, tendons, ligament, cartilage, muscle repair, and other biomedical applications,” Zhang said.

The team has filed a patent and early next year will establish a spin-off company to make three-dimensional scaffolding and other materials for varied applications and for the next stages of testing and research by diverse institutions.

“We are the only group with the technology to make these hybrid materials, and they should have wide commercial applications in medical care,” Zhang said.

For her nanoprobe–chlorotoxin research, Zhang received funding from the National Institutes of Health, the National Cancer Institute, and the National Institute of Biomedical Imaging and Engineering. Her nerve guide research is funded by the National Science Foundation, the National Institutes of Health, and other sources.