We propose to use phage libraries displaying peptides to identify molecules that are specifically or selectively expressed in the vasculature of individual tissues, including tumors. Endothelial cells, which are primarily targeted by our method, are known to differ in their properties in different tissues, but very few of the molecular differences have been identified at this time. Our method, in vivo screening of phage libraries, makes it possible to identify tissue-specific molecular markers of endothelial cells. We have already shown that it is possible to isolate phage clones capable of targeting selectively the brain and kidney after intravenous injection into mice. Peptides synthesized based on the sequences displayed by phage that home to the brain or the kidney compete with the phage for binding, indicating that they bind to the same structures in these tissues. Moreover, preliminary results suggest that it will be possible to identify peptides capable of homing preferentially to tumors rather than normal tissues. In the work proposed here, we will characterize the target molecules for the brain-homing peptides by targeting selective markers expressed in the vasculature of tumor tissues, which typically is undergoing angiogenesis. Peptides with tissue-specific targeting properties could be used to selectively deliver drugs, genes or cells to the vasculature of a tumor, or of a targeted organ. Major advances in tumor therapies could be realized with this technology. Valuable information on the distinguishing characteristics of different vascular beds, including those undergoing angiogenesis, is also likely to ensue.
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