In 2012, approximately 150,000 people will be diagnosed with colorectal cancer (CRC) and 47,000 will die of the disease. The traditional colorectal cancer screening method, endoscopy, is inefficient for colitis-associated cancer (CAC) because of the absence of polyp formation associated with this disease. The flat lesions in CAC can be explained by the APC (adenomatous polyposis coli) mutation occurring at a much later stage when compared to sporadic cancer. Considering that dysplasia arising in colorectal cancer is a superficial disease, optical imaging is ideal for imaging dysplasia in the colon due to its high detection sensitivity, high throughput reporting strategy and low cost. Currently efforts in molecular optical imaging allow in vivo visualization and characterization of biological processes that occur on a sub-cellular level. Use of near-infrared dyes as imaging agents further allows for deeper tissue penetration in the wavelength range of 700-1000 nm due to the minimal absorption of light by tissue in this range. The ultimate goal of this proposal is t develop a novel and clinically translatable approach for early detection of dysplasia in inflammatory bowel disease (IBD)-associated CRC patients. Dysplasia is characterized by alteration in the pattern of cellular arrangement, size and shape of the nuclei, and nuclear- cytoplasmic ratio. These morphological features are sensitive to the polarization signature of light, allowing optical imaging to play a vital role in distinguishing dysplasia versus normal tissue. Also, due to the sequence of mutations associated with the development of cancerous lesions from dysplasia, there is a distinct expression of biomarkers on the surface of the cells. Using molecular probes as imaging agents allows another significant aspect of optical imaging to further contribute towards better detection of pre-cancerous lesions. Conjugation of the Fab fragments with an NIR dye would further allow for deeper tissue penetration complimented with higher detection sensitivity. Based on these considerations, we hypothesize that a near- infrared molecular probe for targeted imaging, in conjunction with a highly sensitive multifunctional fluorescent endoscopic device equipped with polarization imaging capability, will detect dysplasia in CAC with high sensitivity and specificity.
The specific aims of the proposed study are to (1) synthesize and develop a molecular probe that is highly specific for dysplasia in IBD patients;(2) develop a multifunctional fluorescent endoscope with polarization imaging capability to capture both molecular and structural information related to dysplastic IBD tissue;and (3) employ clinically relevant murine models to demonstrate the feasibility of using the molecular probe and multifunctional endoscope for in vivo imaging. Successful completion of the study will facilitate rapid diagnosis and better treatment outcomes for CAC patients. This proposed approach will allow the full realization of the potential of optical imaging for early detection of CRC in IBD patients.
The goal of this proposal is to develop novel molecular probes that are able to bind to dysplasia in inflammatory bowel disease (IBD) patients with high affinity and further develop a multifunctional fluorescent endoscopic device for detecting molecular biomarkers and morphological features in colitis-associated cancer (CAC) patients with high sensitivity and specificity. With the current capabilities of optical imaging for endoscopy in humans, there is a clear path to human translation of the products of this research.