CT Monitoring of Angiogenesis

描述(由申请人提供)：我们的最终目标是改善非侵袭性人类癌症的特征，作为指导针对患者的治疗的一种手段。我们的方法利用了众所周知的肿瘤血管对大分子的普遍渗漏。本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剂(MMCM)，CT是评估体内恶性肿瘤的最常用的临床成像手段。目前所有可用的CT造影剂都很小(1 KDa)，并且从正常和肿瘤微血管中非特异性地渗出到间质中。在大分子(&gt；20 kDa)中可以看到更多的选择性渗漏，它们仍然局限在大多数正常组织的血池中，但从高度扭曲的癌症微血管中渗出。我们精心设计了一种新型的碘化血池CT MMCM，它由易于获得和廉价的部分组成，所有这些部分都曾用于FDA批准的药物，其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”，即聚乙二醇基赖氨酸树枝状大分子与有机结合碘(聚乙二醇三碘)结合是可行的MMCM，可用于在CT的大鼠模型中获得微血管泄漏和血浆体积分数的准确测量。四个“特定目标”的实验**将：(1)确定从这类化合物合成一系列化学纯MMCM的简单性，并评估它们的化学特性；(2)确定合成的MMCM的体内特征，包括用MMCM增强的动态CT的作用大小，以量化血管渗漏对抗血管内皮生长因子抗体的反应的变化，作为选择未来开发的最佳化合物的手段；(3)确定用上述最好的MMCM获得的动态CT扫描是否可以区分不同侵袭性的肿瘤；以及(4)确定最佳化合物的大规模合成是否可行。在我们的roposal完成后，我们最好的MMCM造影剂将在评估动物肿瘤模型的微血管收缩能力变化方面具有被证明的价值，并将提交给NIH资助的DCide计划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。

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.