Nanoparticles Home in on Brain Tumors, Boost Accuracy of Surgical Removal
Using nanoparticles that can be imaged with three different technologies, a research team at Stanford University Center for Cancer Nanotechnology Excellence and Translation has removed brain tumors from mice with unprecedented accuracy. In a study published in the journal Nature Medicine, a team led by Sanjiv Sam Gambhir showed that the nanoparticles engineered in his lab homed in on and highlighted brain tumors, precisely delineating their boundaries and facilitating their complete removal. With further development, these nanoparticles stand to improve the prognosis of patients with deadly brain cancers.
Each year about 3,000 people are diagnosed with glioblastoma, the most aggressive form of brain tumors. The prognosis for glioblastoma is bleak, in large part because it is almost impossible for even the most skilled neurosurgeon to remove the entire tumor while sparing normal brain. "With brain tumors, surgeons don't have the luxury of removing large amounts of surrounding normal brain tissue to be sure no cancer cells are left," said Dr Gambhir. "You clearly have to leave as much of the healthy brain intact as you possibly can."
This is a real problem for glioblastomas, which are particularly rough-edged tumors. In these tumors, tiny fingerlike projections commonly infiltrate healthy tissues, following the paths of blood vessels and nerve tracts. An additional challenge is posed by micrometastases that often dot otherwise healthy nearby tissue but that are invisible to the surgeon's naked eye. Left behind during surgery, these micrometastases will eventually grow into new tumors.
The imaging agent that the Stanford group developed consists of a gold core coated with a Raman imaging agent, a thin layer of protective silica, and an additional coating of stabilized gadolinium, a magnetic resonance imaging (MRI) contrast agent. Today, MRI is used frequently to give surgeons an idea of where in the brain the tumor resides before they operate. MRI is well-equipped to determine a tumor's boundaries. However, when used preoperatively MRI cannot perfectly describe an aggressively growing tumor's position within a subtly dynamic brain at the time the operation itself takes place.
A second, newer method is photoacoustic imaging, in which pulses of light are absorbed by materials such as the nanoparticles' gold cores. The particles heat up slightly, producing detectable ultrasound signals from which a three-dimensional image of the tumor can be computed. Because this mode of imaging has high depth penetration and is highly sensitive to the presence of the gold particles, it can be useful in guiding removal of the bulk of a tumor during surgery.
The third method, called Raman imaging, leverages the ability of the gold nanoparticles to amplify the almost undetectable amounts of light, emitted with a specific spectral fingerprint, given off by the nanoparticle's Raman coating.
To demonstrate the utility of their approach, the investigators first showed via various methods that the lab's nanoparticles specifically targeted tumor tissue, and only tumor tissue. Next, they implanted several different types of human glioblastoma cells deep into the brains of laboratory mice.
After injecting the imaging-enhancing nanoparticles into the mice's tail veins, they were able to visualize, with all three imaging modes, the tumors that the glioblastoma cells had spawned. Prior to surgery, the team used MRI scans to obtain preoperative images of tumors' general shapes and locations. During the operation itself, photoacoustic imaging permitted accurate, real-time visualization of tumors' edges, enhancing surgical precision.
Neither MRI nor photoacoustic imaging by themselves can distinguish healthy from cancerous tissue at a sufficiently minute level to identify every last bit of a tumor. Here, the third method, Raman imaging, proved crucial. In the study, Raman signals emanated only from tumor-ensconced nanoparticles, never from nanoparticle-free healthy tissue. After the bulk of an animal's tumor had been cleared, the highly sensitive Raman-imaging technique was extremely accurate in flagging residual micrometastases and tiny fingerlike tumor projections still holed up in adjacent normal tissue that had been missed on visual inspection. This, enabled these dangerous remnants' removal.
"Now we can learn the tumor's extent before we go into the operating room, be guided with molecular precision during the excision procedure itself, and then immediately afterward be able to 'see' once-invisible residual tumor material and take that out too," said Dr. Gambhir. He also suggested that the nanoparticles' propensity to heat up on photoacoustic stimulation, combined with their tumor specificity, might also make it possible for them to be used to selectively destroy tumors. He also expressed optimism that this kind of precision could eventually be brought to bear on other tumor types.
This work, which is detailed in a paper titled, "A brain tumor molecular imaging strategy using a new triple-modality MRI-photoacoustic-Raman nanoparticle," was supported in part by the NCI Alliance for Nanotechnology in Cancer, a comprehensive initiative designed to accelerate the application of nanotechnology to the prevention, diagnosis, and treatment of cancer. An abstract of this paper is available at the journal's website.