The overall goal of this project is to improve the detection of cancer using an endoscopic imaging approach that incorporates both Raman spectroscopy and nanoparticles. I propose to do this through a novel molecular imaging approach. The molecular imaging will be accomplished by using topically administered tumor targeted gold based nanoparticles that produce a Raman light scattering signal and a Raman endoscope that can excite these nanoparticles with light and detect their inelastically scattered light. I plan to investigate the natural biodistribution of these nanoparticles using a multimodal approach (microPET and intravital microscopy) in living mouse models. Various routes of nanoparticle administration will be investigated using topical application to the oral cavity, bladder, and cervix (all of which have the ability to be interrogated with an endoscope clinically) and compare their distribution to an intravenous injection. It is believed that by administering these gold nanoparticles topically (i.e. oral cavity) that potential adverse toxicity effects wouldbe avoided due to circumventing the circulatory system. I will also microscopically examine the interaction of nanoparticles with open wounds or abscesses that could potentially be in close proximity to the area of interest (i.e. oral cavity) receiving the topical nanoparticle administraton. Once their biodistribution and toxicity effects are more thoroughly understood I plan to evaluate the targeting efficiency of these tumor targeted Raman nanoparticles on fresh human tumor tissue samples. I intend to use squamous cell carcinoma to demonstrate this general approach as the first target for reasons of tumor targeted peptide availability, reduced toxicity and a need for improved detection. The approach is expected to be low risk for clinical translation because Raman endoscopes have previously been used in humans, and because gold based nanoparticles are relatively inert and some constructs have already been approved by the FDA for human use. The results obtained from this proposal could significantly accelerate the translation of this novel strategy into the clinic. In addition, harnessing the ultrasensitive detection and multiplexing capabilities of Raman spectroscopy for the detection of cancer could serve as a powerful diagnostic tool, with the potential to significantly impact the survival rate of cancer patients.