A class of engineered nanoparticles—Raman-silica-gold-nanoparticles—has been shown to be safe when administered by two alternative routes in mouse models, according to a study published April 20 in Science Translational Medicine. This marks the first step up the ladder of toxicology studies that, within a year and a half, could yield to human trials of these agents for detection of colorectal and possibly other cancers.
"These nanoparticles' lack of toxicity in mice is a good sign that they'll behave well in humans," said Sanjiv Sam Gambhir, MD, PhD, professor of radiology at Stanford University School of Medicine, in Stanford, Calif. "Early detection of any cancer, including colorectal cancer, markedly improves survival," said Gambhir. For example, the widespread use of colonoscopy has significantly lowered colon-cancer mortality rates, he said. "But colonoscopy relies on the human eye. So this screening tool, while extremely useful, still misses many cancer lesions such as those that are too tiny, obscure or flat to be noticed."
Raman spectroscopy is an optical imaging method that is based on the “Raman effect,” the inelastic scattering of a photon when energy is absorbed from light by a surface. The underlying gold cores of the Raman-silica-gold-nanoparticles amplifies the "Raman effect," allowing the simultaneous detection of many different imaging materials by the Raman microscope.
"Photoimaging with these nanoparticles holds the promise of very early disease detection, even before any gross anatomical changes show up, without physically removing any tissue from the patient," said Gambhir. Because the researchers are developing these particles for use as targeted molecular imaging agents, Gambhir and colleagues examined the acute toxicity and biodistribution of these nanoparticles in two groups of mice, each consisting of 30 male and 30 female animals, in a variety of ways.
The first group of 60 mice received the nanoparticles rectally. The researchers followed up with a series of measurements at five different time points ranging from five minutes to two weeks. They monitored the test animals' blood pressure, electrocardiograms and white-blood-cell counts. They examined several tissues for increases in the expression of antioxidant enzymes or pro-inflammatory signaling proteins and stained tissues with dyes that flag dying cells.
These inspections yielded virtually no signs of stress to any tissues, and none at all by two weeks after the time of administration. Gambhir and colleagues also found no gold anywhere outside the bowel using electon microscopy, indicating that the nanoparticles remained confined to that organ and thus, when rectally administered, posed no threat of systemic toxicity. Furthermore, the nanoparticles were quickly excreted.
"That lowers the bar for testing of these agents by the FDA for use in detecting colorectal cancers, because it addresses worries about systemic toxicity," Gambhir said.
However, even if the nanoparticles had moved beyond the bowel, it seems they would have caused no systemic problems. On administering the nanoparticles intravenously to the second group of 60 mice, the investigators once again found scant signs of inflammation or other evidence of toxicity—and virtually none by two weeks after administration. The intravenously administered nanoparticles were rapidly sequestered by scavenger cells resident in organs such as the liver and spleen.
This opens the door to human tests of intravenous injections of these nanoparticles to search for tumors throughout the body. "We can attach molecules targeting breast, lung or prostate cancer to these spheres," Gambhir said. Gambhir's group is now filing for FDA approval to proceed to clinical studies of the nanoparticles for the diagnosis of colorectal cancer.
The study was sponsored by the National Cancer Institute and the Canary Foundation.