Nanovectors for Characterization and Destruction of Breast Tumor Vasculature

用于表征和破坏乳腺肿瘤脉管系统的纳米载体

• 批准号: 7503965
• 负责人: MAURO FERRARI
• 金额: $ 39.25万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-28 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7503965
• 关键词: 3-Dimensional; Ablation; Adverse effects; Affinity; Animal Model; Applications Grants; Aptamer Technology; Area; Bacteriophages; Bioinformatics; Biological; Biological Markers; Biomedical Engineering; Biometry; Blood Vessels; Cancer Biology; Cancer cell line; Clinical; Clinical Treatment; Clinical Trials; Computer Simulation; Computers; Cytotoxic agent; Development; Diagnostic Procedure; Doxorubicin; Drug Formulations; Encapsulated; Engineering; Ensure; Evaluation; Flow Cytometry; Fractionation; Gene Delivery; Generations; Goals; Gold; Growth; Health Sciences; Human; In Vitro; Italy; Lesion; Libraries; Ligands; Liposomes; Local Therapy; Localized; Malignant Neoplasms; Malignant neoplasm of pancreas; Mammary Neoplasms; Mass Spectrum Analysis; Medical; Medicine; Methods; Modality; Molecular; Molecular Biology; Molecular Profiling; Molecular Weight; Monitor; Nanomanufacturing; Nanotechnology; Neoplasm Metastasis; Ohio; Oligonucleotides; Patients; Peptides; Phage Display; Pharmaceutical Preparations; Plasma; Process; Proteins; Proteome; Proteomics; RNA Phages; Reporter; Research; Research Personnel; Screening procedure; Serum; Serum Proteins; Signal Transduction; Silicon; Site; Small Interfering RNA; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Staging; Structure; Technology; Testing; Texas; Therapeutic; Therapeutic Agents; Time; Treatment Efficacy; Universities; University of Texas M D Anderson Cancer Center; Validation; Vascular Endothelium; angiogenesis; aptamer; base; case control; chemical synthesis; chemotherapeutic agent; combinatorial; data mining; density; design; desire; experience; improved; in vivo; innovation; malignant breast neoplasm; mathematical model; nanoparticle; nanoparticulate; nanosized; nanovector; novel; particle; phosphorodithioic acid; phosphorothioate; predictive modeling; programs; protein expression; receptor; selective expression; success; targeted delivery; tumor; tumor xenograft; vascular bed

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.

描述（由申请人提供）：血管内皮在乳腺肿瘤的发育和转移过程中既充当屏障又充当靶向位点。我们的应用研究假设是，新型纳米载体捕获与血管生成血管相关的蛋白质，用于选择性地靶向这些结构，并将治疗剂递送到人类乳腺肿瘤周围的血管区室，这提供了颠覆性技术，该技术将克服目前治疗剂从血管区室运输到乳腺肿瘤部位时存在的重大障碍。这项 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、UT-加尔维斯顿医学分部、俄亥俄州立大学和意大利卡坦扎罗麦格纳格雷西亚大学的跨学科、多机构研究人员团队，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及其相关分子特征的目标。 脉管系统，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开发和完善、乳腺癌生物学、分子生物学、使用页面显示方法进行血管靶向、在中性脂质体中开发用于肿瘤靶向的小干扰RNA、开发用于肿瘤靶向的新型适体、脉管系统的3维数学模型、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，提出以下具体目标： 1).使用新型纳米芯片对血清中存在的、由乳腺肿瘤和脉管系统产生的低分子量肽进行分级和洗脱，定义已知和尚未识别的蛋白质。 2）。使用噬菌体展示文库识别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，并使用靶向金噬菌体纳米颗粒组件作为信号报告者和药物/基因递送载体消融乳腺肿瘤脉管系统；和3）。细化多阶段纳米载体与定量计算机模型相结合，选择性地靶向与乳腺肿瘤相关的脉管系统，并结合时间调节的递送方式，以最佳方式克服生物屏障，从而有效破坏乳腺肿瘤及其邻近的脉管系统。