Project Summary The primary goal of this Project is to translate near-infrared optical contrast agents for image-guided bronchoscopy and surgery. When a patient is found to have a lung nodule, the two procedures are a diagnostic bronchoscopy and a therapeutic surgery. However, these two procedures are plagued with problems such as discriminating between cancerous and non-cancerous nodules, finding second cancers, identifying positive margins, and performing an accurate back table pathological assessment. Therefore, the success rate for bronchoscopy and surgery for lung cancer are both around 60%. There are urgent unmet needs to develop new and innovative technologies that can assist the clinician in localizing cancer cells, delineating tumor margins, and identifying micrometastases and draining lymph nodes. We propose a new technology to image patients during standard-of-care bronchoscopy and surgery in order to identify cancerous lesions, to discover residual local disease before completing the procedure, and to render a diagnosis. While the proposed technologies are broadly applicable to solid tumors, this project is specifically committed to improving detection of lung cancer, one of the most aggressive human malignancies. To accomplish this goal, we have assembled a collaborative team at University of Pennsylvania with synergistic expertise in clinical trials, lung pathology, thoracic surgery, and imaging. The proposed work will optimize four distinct types of contrast agents in a combination or cocktail for a translational intraoperative imaging clinical trials. The tracer combination will be evaluated in a first-in-human clinical trial of lung cancer patients in order to determine if there is a benefit of intraoperative imaging to standard-of-care bronchoscopy and surgery. The combination contrast agent strategy will allow better imaging of diseased cells more deeply buried in the tissues. This will allow for precise tumor localization and more accurate resection of cancers without violating the tumor capsule or seeding the body cavity.