Over 50,000 lives are lost annually due to colon cancer, making it the third deadliest cancer in the United States.
The aim of this project is to improve early-stage colon cancer screening using a unique Raman imaging microendoscope to detect molecularly targeted nanoparticles. A scanning Raman endoscope device capable of fast non-contact imaging will be built and used to image targeted silica-encapsulated, gold-based nanoparticles. The particles produce a Raman light scattering signal and will be administered topically to the colon in mixtures that enable ratiometric imaging to subtract out background signal from that targeted particles. The Raman endoscope, using laser light, illuminates the nanoparticles and detects the inelastically scattered light. We will fabricate the circumferential-scanning Raman endoscope to image the colon anatomy with white light as well as colon cancer biomarkers with targeted Raman-active particles. The Raman endoscope has been designed for clinical use but will be evaluated with spontaneous tumors (Pirc rats) and primary human xenografts. De-identified human colon cancer tissues will be procured during routine colonoscopy and surgically implanted into animals. Overexpression of various colon cancer biomarkers will be assessed on these human colon cancer tissues using qPCR, western blot analysis and immunohistochemistry. Selected tumor-targeting ligands, will be used to functionalize the surface of our Raman nanoparticle contrast agents. We will assess tumor targeting efficiency and the performance of our Raman endoscope first in rats and then in large animals (porcine). Although this novel diagnostic strategy is not limited to the colon, we are motivated to validate our approach with colorectal cancer due to the availability of tumor-targeting ligands, endoscope compatibility, reduced toxicity and a real need for improved detection of this malignancy. The approach is expected to be low risk because Raman endoscopes have previously been used in humans and because gold based nanoparticles are relatively inert with some constructs already approved by the FDA. Harnessing the ultrasensitive detection and multiplexing capabilities of Raman spectroscopy for the detection of cancer could serve as a powerful diagnostic tool with the potential to significantly impact the survival rate of cancer patients by earlier cancer detection.

Public Health Relevance

Colonoscopy is one of the few cancer screening procedures that is highly effective in reducing mortality, yet many early lesions still go undetected. Advance in microendoscopic imaging tools and targeted molecular probes may effectively improve detection of these lesions. While fluorescent and colorimetric imaging agents have established utility in intra-operative imaging, these strategies are limited by auto- fluorescence, non-specifi binding, and a lack of multiplexing capacity for concurrent imaging of relevant proteins. We propose to develop an endoscopic optical imaging system that scans the colon wall for functionalized nanoparticles engineered to emit unique optical signatures. These nanoparticles can be functionalized with different targeting molecules that specifically bind to cancerous and precancerous tissues, enabling highly sensitive and specific, quantitative detection of multiple genetic markers simultaneously. Our proposed device operates in the near-infrared spectrum, minimally impacting the standard colonoscopy procedure yet enabling a real-time, complete 'molecular map' of the colon for early detection of colorectal cancer.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Study Section
Medical Imaging Study Section (MEDI)
Program Officer
Nordstrom, Robert J
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Stanford University
Schools of Medicine
United States
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Rogalla, Stephan; Contag, Christopher H (2015) Early Cancer Detection at the Epithelial Surface. Cancer J 21:179-87
Garai, Ellis; Sensarn, Steven; Zavaleta, Cristina L et al. (2015) A real-time clinical endoscopic system for intraluminal, multiplexed imaging of surface-enhanced Raman scattering nanoparticles. PLoS One 10:e0123185