The application of multiphoton microscopy (MPM) to the study of solid tumor biology in vivo has elucidated pathways and mechanisms of cancer progression and has motivated new therapeutic strategies and approaches. Current high-resolution intravital imaging techniques, however, can only be used to visualize tumor microstructure and vascular morphology superficially (300-400 5m depth) and only over volumetric regions that are a fraction of the total tumor volume. Additionally, longitudinal imaging is often limited in frequency due to the accumulation of exogenous contrast agents. Here we propose to purchase a state-of-the- art Doppler Optical Frequency Domain Imaging (OFDI) instrument, which overcomes these limitations of MPM and is a complementary technology. Using Doppler OFDI, we will be able to image a field up to 5.8 mm by 7.8 mm and more than 2 mm deep in 15 minutes, a significant increase both image volume and imaging speed compared to MPM. The imaging technique does not require the use of tracers, allowing for frequent, repeated timepoint measurements. This will accelerate research on our currently funded NIH grants and reduce the cost of our research over the long term. The Doppler OFDI instrument would be dedicated to small animal imaging and housed in the Steele Laboratories at Massachusetts General Hospital, whose mission is to understand the pathophysiology of solid tumors and develop novel, curative therapies for primary and metastatic cancers. The Doppler OFDI instrument will accelerate research on more than ten NIH research grants, including one Program Project Grant, two Bioengineering Research Partnership Grants and 3 R01 grants. Each grant relies upon intravital imaging to probe the growth, invasion and response of tumors to different experimental therapies in animal models. As an example, the Program Project Grant (P01-CA080124) relies upon MPM to monitor vascular normalization in response to different molecular interventions and treatment approaches. Using Doppler OFDI, we will evaluate vascular changes throughout the entire experimental tumor, which would normally require prolonged anesthesia and cumbersome imaging protocols using MPM and would only achieve about 20% of the image depth at best. Furthermore, with Doppler OFDI we will be able to monitor changes in tumor associated lymphatic vessels and changes in tumor tissue viability. Thus Doppler OFDI will facilitate the exploration of physiological and pathological processes and the evaluation of treatment strategies in order to fight the growth and spread of cancer. The facility will be shared by multiple investigators, including scientists from the Departments of Radiation Oncology and Dermatology at MGH, and will be critical for meeting the aims of ongoing NIH-funded projects of these investigators as well as many planned projects. Doppler OFDI will allow critical questions to be addressed that have not been answered due to the lack of this enabling technology and will open new avenues of research that will lead us closer to new therapies for cancer. Public Health Relevance: The ability to monitor and interrogate changes in tumor cell viability, tumor blood vasculature and tumor associated lymphatic vessels is critical to identify successful novel therapeutic approaches to combat the growth and spread of solid cancers. To date, the ability to monitor these parameters with the necessary spatial and temporal resolution has been limited by the current state of the imaging technology. In this application, we propose to purchase a novel state-of-the-art Doppler optical frequency domain imaging instrument, which overcomes many of the limitations of current imaging technologies, for dedicated use in the evaluation of novel anti-cancer therapeutics in small animals.
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