The major hypothesis guiding this research is that fluorescent semiconductor nanocrystals (quantum dots) will be clinically useful reagents for in vivo imaging. As contrast agents, quantum dots offer several advantages over traditional fluorophores including broad absorption bands, extremely high extinction coefficients, quantum yields approaching 50%, photostability at high fluence rate, and high capacity for ligand conjugation. To date, however, quantum dots with optimal properties for in vivo imaging have not been developed. The long-range goal of this research is to improve cancer cell detection and vascular imaging by developing quantum dots with optimal in vivo properties. The R21 phase of the proposal focuses on the design, synthesis, and initial characterization of nearinfrared (NIR) quantum dots. Although invisible to the human eye, the NIR (700 nm to 900 nm) portion of the spectrum is characterized by low autofluorescence, deep tissue penetration, and low tissue scatter of light. Using a model that incorporates both tissue and quantum dot photonic properties, we have predicted the absorption and emission characteristics of """"""""optimal"""""""" NIR quantum dots. We describe strategies to synthesize such contrast agents, and present preliminary data of how NIR quantum dots might be expected to perform in vivo by using an intraoperative imaging technique recently developed by our laboratory. The R33 phase of the proposal focuses on the in vivo characterization of NIR quantum dots. Two distinct clinical applications are explored: cancer cell detection/imaging and vascular imaging. Our laboratory has developed prostate and bladder cancer-specific low-molecular weight ligands that can be used to target contrast agents to tumor cells (see Preliminary Studies). We propose to conjugate these ligands to NIR quantum dots and to characterize their biodistribution, pharmacokinetics, and tumor localization. It is hypothesized that such contrast agents will provide unparalleled improvements in cancer cell detection in vivo. We also propose to optimize NIR quantum clots for intraoperative vascular imaging and image-guided delivery of cardiac gene therapy using animal models of cardiac ischemia and necrosis. If completed, the specific aims of this proposal will generate a clinically useful set of contrast agents, and a more complete understanding of the in vivo behavior of fluorescent semiconductor nanocrystals.
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