CT Monitoring of Angiogenesis

血管生成的 CT 监测

• 批准号: 7625249
• 负责人: BENJAMIN M YEH
• 金额: $ 46.13万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7625249
• 关键词: Aftercare; Animals; Antibodies; Basic Science; Binding; Biological Effect of Chemicals; Blood; Blood Plasma Volume; Blood Vessels; Breast Cancer Model; Calculi; Characteristics; Chemicals; Clinical; Clinical Trials; Dendrimers; Development; Extravasation; FDA approved; Flowcharts; Funding; Future; Goals; Grant; Human; Immunohistochemistry; Iodine; Lysine; Malignant Neoplasms; Measurement; Measures; Microvascular Permeability; Modality; Modeling; Modification; Monitor; Neoplasms in Vascular Tissue; Normal tissue morphology; Osmolalities; Patients; Pharmacologic Substance; Polyethylene Glycols; Process; Property; Radionuclide Imaging; Rattus; Research; Research Personnel; Roentgen Rays; Route; Scanning; Solubility; Testing; Time; Toxic effect; Toxicology; Transferrin; Vascular Permeabilities; Viscosity; Weight; X-Ray Computed Tomography; angiogenesis; attenuation; base; bevacizumab; density; design; improved; in vivo; interstitial; macromolecule; meetings; molecular size; novel; programs; research study; response; scale up; tumor

DESCRIPTION (provided by applicant): Our ultimate goal is to improve non-invasive human cancer characterization as a means to direct patient- specific therapy. Our approach takes advantage of the well documented universal leakiness of tumor blood vessels to macromolecules. The goal of this project is to develop a macromolecular contrast material (MMCM) which can be used safely in vivo with computed tomography (CT), which is the most commonly used clinical imaigng modality for assessing malignancy in the body. All currently available CT contrast materials are small in size (< 1 kDa) and leak out nonspecifically from both normal and tumor microvessels into the interstitial space. More selective leakage is seen with macromolecules (> 20 kDa), which remain confined in the blood pool in most normal tissues but leak out of the highly distorted microvessels of cancers. We have carefully designed a novel class of iodinated blood-pool CT MMCM that is composed of easily obtainable and inexpensive moieties, all of which have previously been used in FDA approved Pharmaceuticals, with expandable components that allow for precise size adjustment during synthesis. This project will test the "OVERALL HYPOTHESIS** that polyethylene glycol-based lysine dendrimers conjugated with organically bound iodine (PEG-triiodo) are feasible MMCMs that can be used to obtain accurate measurements of microvascular leakiness and fractional plasma volume in a rat model at CT. Experiments in the four "SPECIFIC AIMS** will: (1) Determine the simplicity of synthesis for an array of chemically pure MMCM's from this class of compound and evaluate their chemical characteristics; (2) Determine the in vivo characteristics of the synthesized MMCM's, including the effect size of dynamic CT enhanced with the MMCMs to quantify changes in vascular leakiness in response to anti-VEGF antibody as a means to choose the best compound for future development; (3) Determine whether dynamic CT scans obtained with the best MMCM identified above can differentiate between tumors of different aggressiveness; arid (4) Determine whether large-scale synthesis of the optimal compound is feasible. On completion of our >roposal, our best MMCM contrast material will have proven value for assessing changes in microvascular jermeability in animal tumor models and will be submitted to the NIH-funded DCIDE program for formal >reclinical toxicology assessment as a stepping stone to applying for FDA approval for clinical trials.

描述（由申请人提供）：我们的最终目标是改善非侵入性人类癌症表征，作为指导患者特异性治疗的手段。我们的方法利用了有据可查的肿瘤血管对大分子的普遍渗漏性。该项目的目标是开发一种可在体内安全地与计算机断层扫描（CT）一起使用的大分子造影材料（MMCM），计算机断层扫描（CT）是评估体内恶性肿瘤最常用的临床成像方式。目前所有可用的 CT 造影材料尺寸都很小 (< 1 kDa)，并且会从正常微血管和肿瘤微血管非特异性渗漏到细胞间隙中。大分子（> 20 kDa）会出现更多选择性渗漏，这些大分子仍然限制在大多数正常组织的血池中，但会从高度扭曲的癌症微血管中渗漏出来。我们精心设计了一种新型的碘化血池 CT MMCM，它由易于获得且价格低廉的部分组成，所有这些部分之前都已用于 FDA 批准的药物，并具有可扩展的组件，允许在合成过程中精确调整尺寸。该项目将测试“总体假设**，即基于聚乙二醇的赖氨酸树枝状聚合物与有机结合碘 (PEG-三碘) 结合，是可行的 MMCM，可用于在 CT 下精确测量大鼠模型中的微血管渗漏性和血浆体积分数。四个“具体目标**”中的实验将：(1) 确定 从此类化合物合成一系列化学纯的 MMCM 并评估其化学特性； (2) 确定合成的 MMCM 的体内特性，包括用 MMCM 增强的动态 CT 的效应大小，以量化响应抗 VEGF 抗体的血管渗漏变化，作为为未来开发选择最佳化合物的手段； (3) 确定使用上述确定的最佳 MMCM 获得的动态 CT 扫描是否可以区分不同侵袭性的肿瘤； (4)确定最佳化合物的大规模合成是否可行。完成我们的提案后，我们最好的 MMCM 对比材料将具有评估动物肿瘤模型微血管流动性变化的价值，并将提交给 NIH 资助的 DCIDE 项目进行正式的临床毒理学评估，作为申请 FDA 批准临床试验的垫脚石。