Surface-Enhanced Raman Spectroscopy: A New Modality for Cancer Imaging

Abstract

Although surface-enhanced Raman scattering (SERS) spectroscopy has traditionally been used as an in vitro analytic tool, in the past few years the first reports of the feasibility of in vivo imaging of cancer with biocompatible SERS probes have emerged. SERS imaging has great potential in the field of medical imaging because it offers several major advantages over other molecular imaging methods. Medical imaging using SERS nanoprobes can yield higher sensitivity and higher signal specificity than other imaging modalities, while also offering multiplexing capabilities that allow for unique applications. This article reviews the principles of SERS and highlights recent advances for in vivo cancer imaging. To present the abilities of this method as accurately as possible, the discussion is limited to studies in which the imaging data were confirmed by histological correlation.

Keywords: Raman; SERS; cancer; imaging; nanoparticles.

Figure 1

Principle of surface-enhanced Raman scattering nanoparticles for in vivo cancer detection. (A) Left: Light scattering from a molecule includes both Rayleigh and Raman scattered photons. Middle: Schematic depiction of photon energy transitions during different types of light scattering. Rayleigh scattering is by far the most common form of light scattering, with only few photons undergoing Raman related transitions. Right: Raman spectra exhibit peaks specific to the molecular bond vibrations. Sharp, high-intensity peaks are characteristic of SERS probes. (B) SERS probes can be engineered to create strong SERS signals detectable in vivo. While there are different routes of administration depending on the tumor location and type, in most cases intravenous injection (left) will be the most desirable route. Left inset: SERS probes typically consist of a noble metal core (gold or silver) that provides signal intensity enhancement via surface plasmon resonance effects, a layer of a Raman reporter molecule that gives a specific spectrum, and a passivation layer. Middle: To enable cancer detection, SERS probes must accumulate in cancerous tissue, where they can be detected by their spectral signature upon interrogation with a Raman imaging system. Right: By color-coding the pixels in an acquired image where the unique SERS spectrum of the probe is detected, an image of the tumor is generated.

Figure 2

Imaging of cancer with microscopic precision using a new generation of Raman nanoparticles. (A) SERRS-nanostars. Left: Diagram, 3D rendering and electron microscopy images. SERRS-nanostars consist of a star-shaped gold core surrounded by a near-infrared Raman reporter and a silica shell that is produced without the use of surface primers. Right: phantom with decreasing concentrations of SERRS-nanostars, acquired using in vivo imaging settings. The detection threshold is approximately 1.5 femtomolar (fM). (B, C) After intravenous injection of only 30 fmol/g, SERRS-nanostars enable visualization of microscopic infiltration at tumor margins and regional satellite metastases. Experiments were performed in a human dedifferentiated liposarcoma mouse model. SERRS images were acquired 16–18 h after injection, and signal intensity is displayed in counts/s. (B) Imaging of residual cancer in the resection bed. A SERRS image (left) of the resection bed was acquired after surgical excision of the bulk tumor. The resection was guided by white light only, with the surgeon being blinded to the SERRS images. Immunohistochemistry (IHC) correlation (middle, right) confirmed that the SERRS positive signal (arrows 1 and 2) represented microscopic residual cancer at the margins of the resection bed. IHC images on the far right are magnified views of the areas indicated with arrows 1 and 2. (C) Imaging of regional satellite micrometastases. In a different mouse bearing a liposarcoma, a SERRS image (left) was acquired approximately 1 cm adjacent to the visible margin of the tumor. Note multiple small foci of Raman signal (arrows 1 to 5). As confirmed by IHC (middle, right), each of these five foci correlated with a separate tumor cell cluster (vimentin+) as small as 100 µm (micrometastases). Images on far right are magnified views of the metastases labeled 4 and 5. Adapted, with permission, from reference (10).

Figure 3

Multimodal SERS nanoparticles for pre- and intraoperative imaging of malignant brain tumors. (A) Triple-modality nanoparticle imaging concept. Top: the nanoparticle is detectable by SERS, photoacoustic and MR imaging. Nanoparticles are injected intravenously and home to the brain tumor but not to healthy brain tissue. Bottom: because of the stable, long-term internalization of the nanoparticles within tumor tissue, pre-operative MRI for staging and intraoperative imaging with SERS and photoacoustic imaging can be performed with a single injection. (B) SERS-guided brain tumor resection in living mice. Top: intraoperative photographs show the sequential resection steps, and SERS imaging shows the corresponding residual tumor tissue at each resection step. Of note, after gross total resection, there is persistent SERS signal in the normal-appearing resection bed, suggesting the presence of residual cancer (white dashed square). Bottom: subsequent histological analysis of the tissue containing these SERS-positive foci demonstrates residual cancer tissue invading into the surrounding normal brain. Adapted, with permission, from reference (7).

Figure 4

Potential clinical applications of SERS nanoparticles. (A) Raman imaging systems that allow wide field of view coverage are currently in development (12) and could be used in the operating room to visualize tumor margins, microscopic tumor infiltrations, and loco-regional metastases. (B) Raman deep-tissue imaging endoscopes using surfaced enhanced spatially offset Raman spectroscopy (SESORS) technology (27) could be used for detection of cancers such as pancreatic (top) or prostatic (bottom) cancers. (C) Cancer types located within several centimeters of the skin surface, such as breast cancer, could be detected noninvasively through the skin with SESORS detectors. (D) Raman endoscopes (28) have the potential to be used in endoscopic, laparoscopic, or robotically assisted tumor resections. Expanded, with permission, from reference (10)