CT Monitoring of Angiogenesis

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特征，作为指导患者特异性治疗的手段。我们的方法充分利用了肿瘤血管对大分子的普遍渗漏。该项目的目标是开发一种大分子造影剂（MMCM），可以在体内安全地与计算机断层扫描（CT）一起使用，这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造影剂尺寸都很小（< 1kda），并且从正常和肿瘤微血管非特异性地渗漏到间隙中。在大多数正常组织中，大分子（bbb20 kDa）仍然局限在血池中，但从高度扭曲的癌症微血管中泄漏出来，可见选择性渗漏更多。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，所有这些部分以前都曾用于FDA批准的药物中，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”，即聚乙二醇基赖氨酸树状大分子结合有机结合碘（peg -三碘）是可行的MMCMs，可用于在CT大鼠模型中获得微血管泄漏和分数血浆体积的精确测量。四个“SPECIFIC AIMS**”的实验将：(1)确定从该类化合物中合成一系列化学纯MMCM的简单性，并评估其化学特性；(2)确定合成的MMCM的体内特性，包括MMCM增强的动态CT效应大小，量化抗vegf抗体对血管渗漏的影响，以选择未来开发的最佳化合物；(3)确定采用上述最佳MMCM获得的动态CT扫描是否能够区分不同侵袭性的肿瘤；(4)确定最优化合物的大规模合成是否可行。在>提案完成后，我们最好的MMCM造影剂将被证明具有评估动物肿瘤模型微血管可渗透性变化的价值，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临床试验批准的垫脚石。

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.