Abstract
A new nanoparticle design may make cancer detection possible without the use of molecular markers of tumor cells. The star-shaped probe detected five different cancers in mouse models, according to a new study. By using nanostars to boost surface-enhanced resonance Raman scattering signals, the technique highlighted tumor margins, microscopic metastases, and even precancerous cells with high precision.
Most cancer imaging techniques rely on probes linked to tumor-specific targets. New research has shown that one nanoparticle without ligands can detect five different cancers in mice. These “nanostars” boost surface-enhanced resonance Raman scattering signals enough to visualize tumor margins, microscopic metastases, and even precancerous cells.
“With this ultra-bright probe, we can now really see cancer, no matter how small, no matter what type,” says Moritz F. Kircher, MD, PhD, a radiologist at Memorial Sloan Kettering Cancer Center in New York, NY, and senior investigator in the study (Sci Transl Med 2015;7:271ra7).
A schematic representation of surface-enhanced resonance Raman scattering nanostars. Given their unique shape and resonance, the nanostars were 400 times more sensitive in detecting cancer than their non-resonant, spherical counterparts.
A schematic representation of surface-enhanced resonance Raman scattering nanostars. Given their unique shape and resonance, the nanostars were 400 times more sensitive in detecting cancer than their non-resonant, spherical counterparts.
In Raman imaging, a laser beam hits the nanostars and generates a unique scatter pattern. “Reporter” molecules embedded within the nanoparticle shift how the incoming photons scatter, creating a spectral “fingerprint” that wouldn't normally be found in the body. Then a camera records the spectra and transforms them into spots of light. Unlike normal cells, tumor cells preferentially draw in nanostars through an enhanced uptake process called macropinocytosis, says Kircher. Therefore, no specific targets are needed for Raman imaging to expose cancer hiding in tissue that looks healthy.
In previous work, Kircher and his colleagues used sphere-shaped nanoparticles with Raman imaging to precisely outline glioblastomas in mice. However, for reasons that aren't yet fully understood, other tumor types don't always accumulate enough nanospheres to generate sufficient light.
To improve the chances of “seeing” cancers that contain low probe concentrations, Kircher redesigned the nanoparticle and increased Raman signals 400-fold. Innovations included changing the gold core into a star shape, which helped concentrate the signal at each pointed tip. The new geometry also shifts absorbed light to the near-infrared region, further strengthening the signal by making it resonate at wavelengths that are shared by the laser, the gold core, and the red dye Raman reporter that coats the gold core.
Four transgenic mouse models of cancer and one human sarcoma xenograft model were used to evaluate the nanostar probe. Researchers chose models that mimic tumor growth in human cancers known to have high incidence, morbidity, mortality, or recurrence: breast cancer, pancreatic ductal adenocarcinoma, prostate cancer, and sarcoma. Each test group, which included four to seven mice, received 30 fmol/g intravenous injections of nanostars.
After waiting 16 to 18 hours for the nanostars to clear general circulation and become internalized by tumor cells, surgeons excised the tumors identified by routine light imaging. Researchers then examined the remaining normal-appearing mouse tissue with Raman imaging and compared the results from that analysis with histopathologic findings. In every instance, Raman imaging revealed neoplastic cells that careful surgical resection had left behind. Furthermore, two of the mouse models—for pancreatic and prostate neoplasia—also revealed nanostars in surrounding epithelial cells. These intraepithelial foci were histologically confirmed as premalignant stages known to progress to invasive cancers.
“This is a big step forward,” says Adam de la Zerda, PhD, an assistant professor of structural biology at Stanford University School of Medicine in Palo Alto, CA, who was not involved in this study. Fluorescence imaging methods rely on biological molecules, whereas “the benefit of Raman is that our bodies produce absolutely no similar signal,” de la Zerda says. “We want to be able to detect these rogue cancer cells when they invade neighboring tissue. This technique has the potential to do that.”
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