Project Summary/Abstract Non-small cell lung cancer (NSCLC) is a devastating disease with a poor outcome. When a patient is first diagnosed with NSCLC, the person would typically undergo diagnostic bronchoscopy and/or therapeutic surgery. These two procedures have technical challenges that limit their success such as inaccurate biopsies, failure to locate nodules and lymph nodes, missed occult tumors, and positive margins. As a consequence, there is a 40% failure rate for these procedures. This Project will use optical imaging in the near-infrared (NIR) range to generate practical solutions to these problems and make these two common procedures safer, more efficient, and have improved outcomes. The goal of this Project is to test the hypothesis that intraoperative imaging in the NIR spectrum with targeted molecular tracers can identify tumor cells in order to improve procedures that are utilized for the management of patients with NSCLC. The innovation of this Program Project will be in the matrix of cocktail dye development, new NIR camera devices, and clinical translation. There are three specific goals of this Project. First, to develop a set of targeted near-infrared molecular imaging contrast agents that are sensitive and specific to a range of distinct targets on NSCLC. Second, to develop and integrate highly NIR spectral sensitive imaging platforms into commonly used white light imaging devices so they can be utilized during clinical procedures. And third, to apply these innovations to solve common clinical problems in order to impact patient care. If successful, the molecular optical imaging solution presented in this proposal would be immediately applicable to several hundred thousand lung cancer patients each year.