The vascular endothelium functions both as a barrier and as a targeting site during development and metastasis of breast tumors. The HYPOTHESIS for studies in our application is that novel nanovectors to capture proteins associated with angiogenic blood vessels for use to selectively target these structures and to deliver therapeutic agents to vascular compartments surrounding human breast tumors provides disruptive technology that will overcome the significant barriers that are currently present in transport of therapeutic agents from the vascular compartment to the site of breast tumors. This BRP R01 proposal brings together an interdisciplinary, multi-institutional team of established investigators from University of Texas Health Sciences Center, UT-MD Anderson Cancer Center, UT-Medical Branch at Galveston, The Ohio State University, and the University Magna Graecia, Catanzaro, Italy who collectively have expertise in all of the necessary areas to achieve the goals of identifying molecular signatures of breast tumors and their associated vasculature to enable targeting and destruction of breast tumors and blood vessels using nanovectors. The areas of expertise include nanovector development and refinement, breast cancer biology, molecular biology, vascular targeting using page display approaches, development of small interfering RNAs in neutral liposomes for tumor targeting, development of novel aptamers for tumor targeting, 3-dimensional mathematical modeling of the vasculature, proteomics using Mass Spectrometry, biostatistics and data mining. To accomplish these goals, the following Specific Aims are proposed: 1). Define known and as yet unidentified proteins using novel nanochips for fractionation and elution of low molecular weight peptides present in serum, and produced by breast tumors and vasculature. 2). Identify molecular signatures associated with angiogenic processes within the vasculature and serum peptidome of the breast tumor microenvironment using phage display libraries and ablate breast tumor vasculature with targeted gold-phage nanoparticle assemblies as signal reporters and drug/gene delivery carriers; and 3). Refine multi-stage nanovectors combined with quantitative computer modeling to selectively target the vasculature associated with breast tumors combined with time-regulated delivery modalities to optimally overcome the biobarriers for effective destruction of breast tumors and their adjacent vasculature. ? ? ?
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