A novel nanoparticle that is detectable at picomolar concentrations by MRI, photoacoustic imaging, and Raman imaging can accurately identify the margins of brain tumors.

Triple-modality imaging may allow more precise surgery

Surgical treatment of brain tumors requires very precise resection of the tumor: missing malignant tissue could result in a recurrence of the cancer, while removing too much normal tissue can mean unnecessary impairment. However, current imaging methods are limited by insufficient sensitivity and resolution.

Sanjiv S. Gambhir, MD, and colleagues at Stanford University, Memorial Sloan-Kettering Cancer Center, and Weill Cornell Medical College developed a novel nanoparticle tailored for a combination of imaging modalities that can accurately identify the margins of brain tumors. In a report in Nature Medicine, the researchers showed that the approach worked in living mice for both preoperative planning and intraoperative imaging of tumors.

The nanoparticle is detectable at picomolar concentrations by MRI, photoacoustic imaging, and Raman imaging. MRI is already a standard presurgical imaging technique, whereas photoacoustic and Raman imaging are optical imaging techniques that can easily be used intraoperatively.

Photoacoustic imaging penetrates deep into tissue and provides relatively high resolution. It uses light pulses to excite molecular imaging agents, causing thermal expansion with minimal heat production. The thermal expansion produces ultrasound waves detectable by an ultrasound transducer, which constructs a 3D image of the agent's distribution—and hence, of the tumor.

In Raman imaging, detection of light produced by Raman scattering off the nanoparticles allows very specific and sensitive imaging of the tumor margins.

The nanoparticle consists of a 60-nm gold core covered with a thin Raman-active outer layer. This is protected by a 30-nm silica coating, and the particle is then coated with gadolinium as the MRI contrast agent. The particle diffuses through the tumor-disrupted blood–brain barrier and accumulates in tumor cells. It is too large to cross intact blood vessels, so it does not accumulate in healthy brain tissue.

Using glioblastoma-bearing mice, the scientists detected the nanoparticles by the 3 techniques. They also showed that the probe was retained in the tumor for several days following a single injection, allowing lower doses of gadolinium than currently required for both presurgical and intraoperative MRI. “The beauty of it is you inject the particles just once,” Gambhir says.

In surgery on the mice, the team employed MRI for preoperative detection and surgical planning, photoacoustic imaging to guide bulk tumor resection intraoperatively, and Raman imaging to remove residual microscopic tumor infiltrates. “We were pleasantly surprised that this particle does such a good job,” Gambhir says. His group has since studied other particles with different shapes and charges, and none has performed as well as this first particle.

The particles can be easily and inexpensively manufactured in large quantities because variations of them are already used in special inks to deter counterfeit currency, Gambhir says. His lab and several others are developing handheld photoacoustic and Raman imaging instruments that can be inserted into endoscopes and used in surgery. Gambhir hopes the particles could enter trials in patients with late-stage brain cancer in about 3 years.