Nanoparticles Highlight Tumor Borders During Brain Surgery

Using a handheld Raman scanner and nanosized contrast agents that accumulate in brain tumors, surgeons detected and removed tiny, deadly clusters of cancer cells in mice that were not visible to the naked eye (ACS Nano 2014, DOI: 10.1021/nn503948b). If the contrast agent is proven safe for use in people, the technique could help doctors do a more thorough job of removing brain tumors and improve patient survival.

Most patients with brain tumors called glioblastomas die within 15 months of diagnosis, even after surgery. Microscopic clusters of cancer cells remain after surgery and reseed the tumor. “There is cancer recurrence at the surgical site in almost all cases of advanced-stage glioblastoma,” says Moritz F. Kircher, a radiologist at Memorial Sloan Kettering Cancer Center. “Surgeons work by look and feel—the tumor is hard—but it’s hard to find the tumor margins.”

Researchers want to develop imaging techniques that can spot these cells at the margins while a surgeon is operating. Some groups have focused on Raman imaging because, in theory, tumor and healthy tissue produce unique, characteristic Raman signals. In practice, however, analyzing the differences between these signals in patients is difficult and can take hours—much too slow a process to use during surgery.

So Kircher has been developing a Raman contrast agent to help surgeons spot tumor tissue in real time. Kircher’s contrast agent is a 120-nm-diameter sphere consisting of a dye-coated gold core wrapped in a silica crust. The gold enhances the Raman signal of the dye molecules, which serve as Raman reporters for wherever the particles accumulate. The silica crust protects this dye coating from the surrounding biological environment.

In previous work, Kircher and colleagues demonstrated that similar nanoparticles accumulate in mouse glioblastomas and can help visualize tumor cells under a Raman microscope (Nat. Med. 2012, DOI: 10.1038/nm.2721). However, Kircher says, using a Raman microscope during surgery is cumbersome and provides the surgeon with a limited angle of view.

Kircher wanted to see if the contrast agent would work with a handheld Raman scanner—a device resembling a laser pointer on a cord that is more operating-room friendly. In the new study, neurosurgeons performed tumor resection on mice with glioblastoma tumors, using either their naked eyes and white light—as they do in the clinic—or the nanoparticle contrast agent and a handheld Raman scanner. The day before the surgery, the researchers injected the contrast agent into the mice. During the procedure, the surgeons held the scanner over the surgical field. They could look up at a screen displaying a real-time Raman image, with bright spots indicating the presence of the nanoparticles. The researchers also imaged the mice’s brains using a Raman microscope.

During the operation, surgeons using the handheld system found small clusters of cancer cells that weren’t visible under white light or under the Raman microscope. After the surgery, researchers examined stained slices of the brain tissue under an optical microscope and found no detectable cancer cells remaining in the mice that were operated on using the new method.

This kind of real-time imaging would be helpful for many kinds of cancer surgeries, says Shuming Nie of Emory University and Georgia Institute of Technology, who is also developing Raman contrast agents. He hopes that biomedical companies will pick up these contrast agents to determine whether the particles are safe for use in people and can be manufactured at a large scale—two types of tests beyond the capabilities of most academic labs.