This proposal is a multidisciplinary program involving researchers from the Departments of Bioengineering, Chemistry, Pathology and Medicine at the University of Washington. The objective is to develop and validate a new class of molecular nano contrast agents based on biocojugatible gold nanocages for improving the ability of optical coherence tomography (OCT) in early cancer detection. Cancers develop over a period of several years and experience molecular and structural changes prior to metastasis. Early cancer detection remains a critical clinical objective to improve survival rates and treatment outcomes. OCT is a recently developed non-invasive technique that can perform "optical biopsy" by cross-sectional imaging of tissue microanatomy in vivo and in real time. OCT offers excellent spatial resolution;however, currently it has limited success in early cancer detection mainly because of the weak intrinsic optical contrast between normal tissue and early cancer and its lack of molecular specificity. The hypothesis of this proposal is that novel molecular contrast agents can enhance OCT imaging contrast and molecular specificity for early cancer detection. Unlike other metallic nanoparticles, gold nanocages exhibit very strong, tunable optical resonance in the near infrared range while remaining a small size (35-65 nm). Gold nanocages can provide both intensity and spectroscopic contrast enhancement for OCT imaging and they permit facile conjugation of molecular recognition agents for targeting. The specific aims are to: (1) develop gold nanocages with strong absorption or scattering in the near-infrared range using galvanic replacement nanochemistry and optimize synthesis conditions for scaling-up production;(2) characterize the optical properties of nanocages, compare the results with theoretical calculations based on discrete dipole approximation, and quantify intensity and spectroscopic OCT contrast enhancement;(3) perform in vivo animal model studies to quantitatively evaluate the ability of OCT for early cancer detection with assistance of bioconjugated nanocages;and (4) investigate the ability of OCT in detecting dysplasia and early cancer on human esophagectomy specimens using molecular contrast agents. If successful, molecular contrast enabled OCT can improve our ability to detect early cancers, guide biopsy and cancer surgery. In addition, the molecular contrast agents can also be used for other optical imaging and spectroscopy techniques.