Nanovectors for Characterization and Destruction of Breast Tumor Vasculature

描述(申请人提供)：血管内皮细胞在乳腺肿瘤的发展和转移过程中既是屏障又是靶点。我们应用研究的假设是，新型纳米载体捕获与血管新生血管相关的蛋白质，用于选择性地靶向这些结构，并将治疗剂输送到人类乳腺肿瘤周围的血管间，提供了颠覆性技术，将克服目前从血管间到乳腺肿瘤部位的治疗剂运输中存在的重大障碍。BRP R01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、德克萨斯大学加尔维斯顿分校、俄亥俄州立大学和意大利卡塔萨罗的Magna Graecia大学的资深研究人员组成的跨学科、多机构团队，他们共同拥有所有必要领域的专业知识，以实现确定乳腺肿瘤及其相关血管的分子特征的目标，从而能够使用纳米矢量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PAGE显示方法的血管靶向、在中性脂质体中开发用于肿瘤靶向的小干扰RNA、用于肿瘤靶向的新型适配子的开发、血管系统的三维数学建模、使用质谱仪的蛋白质组学、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)。使用新的纳米芯片定义已知和尚未识别的蛋白质，用于分离和洗脱存在于血清中的、由乳腺肿瘤和血管系统产生的低分子多肽。2)。使用噬菌体展示文库识别与乳腺肿瘤微环境的血管生成过程和血清多肽相关的分子特征，并以靶向金噬菌体纳米颗粒组件作为信号报告和药物/基因输送载体来消融乳腺肿瘤血管；以及3)。优化多阶段纳米载体，结合定量计算机建模，选择性地靶向与乳腺肿瘤相关的血管系统，结合时间调节的递送方式，以最佳方式克服生物屏障，有效破坏乳腺肿瘤及其邻近的血管系统。

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.