Biological Modification of Quantum Dots for in vivo Imaging

Stanford University, Stanford CA

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Abstract

Cancer originates in fundamental genetic alterations in tumor cells, leading to changes in protein expression[unreadable] and function, finally resulting in characteristic "signatures" in the serum and on tumor cell surfaces. Powerful[unreadable] proteomics efforts are identifying sets of biomarkers that are characteristic of a tumor's innate biology, which[unreadable] will be important for prediction and monitoring of response to therapy. Since cancer development is a[unreadable] complex process requiring mutation and altered expression of multiple genes, full determination of the[unreadable] biological state and treatment susceptibility of a tumor will require assessment of numerous biomarkers in[unreadable] vivo. To address this issue, we turn to quantum dots (Qdots), which are tiny fluorescent nanocrystals that[unreadable] can be produced with a spectrum of defined emission wavelengths, for generation of multiplex detectors for[unreadable] biomarkers. In Aim 1, antibodies specific for well characterized biomarkers in prostate cancer and[unreadable] lymphoma, will be engineered and coupled to near-infrared Qdots developed in Project 5. Biophysical,[unreadable] biochemical, and biological properties of these tumor-specific Qdots. In Aim 2, we will[unreadable] extend the platform by using cell-surface markers in prostate cancer identified by Project 4, to produce[unreadable] recombinant targets and select novel antibodies by phage display for coupling to Qdots for multiplex imaging[unreadable] of multiple markers. Aim 3 will focus on biological modification of Qdots for targeting the alpha-v-beta3 integrin[unreadable] expressed on tumors and tumor neovasculature, using Arg-Gly-Asp peptides that bind specifically to this[unreadable] protein. Finally, in Aim 4 a strategy for amplifying Qdot signals will utilize coupling to peptides that will[unreadable] enhance cellular uptake, when their activity is unmasked by tumor-specific proteases. Throughout the[unreadable] project period, tumor-targeting Qdots will be provided for in vivo imaging in mouse therapy[unreadable] models of human cancer, to validate their utility. Tumor-specific Qdots will be invaluable reagents in cell[unreadable] biology and preclinical models, for in vivo, real time monitoring of tumor cell activity and function.[unreadable] Furthermore, the targeting strategies developed here can be extended to in vivo delivery of other classes of[unreadable] nanoparticles for alternative modes of detection or for therapy. A sophisticated understanding of the[unreadable] differences between tumor and normal tissues in living organisms will advance our understanding of how to[unreadable] detect and treat cancer.