Nanovectors for Characterization and Destruction of Breast Tumor Vasculature

描述（由申请人提供）：在乳腺肿瘤的发展和转移过程中，血管内皮既作为屏障又作为靶点。我们申请中的研究假设是，捕获与血管生成血管相关的蛋白质以用于选择性靶向这些结构并将治疗剂递送至人乳腺肿瘤周围的血管区室的新型纳米载体提供了突破性技术，该技术将克服目前存在于将治疗剂从血管区室转运至乳腺肿瘤部位中的显著障碍。该BRP R 01提案汇集了来自德克萨斯大学健康科学中心、UT-MD安德森癌症中心、俄亥俄州州立大学加尔维斯顿的UT-Medical分支和卡坦扎罗的Magna Graffin大学的跨学科、多机构研究者团队意大利，他们共同拥有所有必要领域的专业知识，以实现识别乳腺肿瘤分子特征及其相关的脉管系统，从而能够使用纳米载体靶向和破坏乳腺肿瘤和血管。专业领域包括纳米载体的开发和改进，乳腺癌生物学，分子生物学，使用页面显示方法的血管靶向，在中性脂质体中开发小干扰RNA用于肿瘤靶向，开发新型适体用于肿瘤靶向，脉管系统的三维数学建模，使用质谱的蛋白质组学，生物统计学和数据挖掘。为了实现这些目标，提出了以下具体目标：1）。使用新型纳米芯片对血清中存在的低分子量肽进行分级和洗脱，并由乳腺肿瘤和血管系统产生，从而定义已知和尚未鉴定的蛋白质。2）。使用噬菌体展示文库鉴定与乳腺肿瘤微环境的脉管系统和血清肽组内的血管生成过程相关的分子特征，并用靶向金-噬菌体纳米颗粒组装体作为信号报告分子和药物/基因递送载体消融乳腺肿瘤脉管系统;和3）。优化多级纳米载体结合定量计算机建模，以选择性靶向与乳腺肿瘤相关的脉管系统，结合时间调节递送方式，以最佳方式克服生物载体，有效破坏乳腺肿瘤及其邻近脉管系统。

DESCRIPTION (provided by applicant): 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.