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表征，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泄漏。本项目的目标是开发一种可与计算机断层扫描（CT）安全地在体内使用的大分子造影剂（MMCM），CT是评估体内恶性肿瘤最常用的临床影像学方式。所有目前可用的CT造影剂尺寸都很小（< 1 kDa），并且从正常和肿瘤微血管非特异性地泄漏到间质空间中。在大分子（> 20 kDa）中观察到更多的选择性渗漏，其在大多数正常组织中保持限制在血池中，但从癌症的高度扭曲的微血管中渗漏出来。我们精心设计了一种新型的碘化血池CT MMCM，其由易于获得且廉价的部分组成，所有这些部分先前都已用于FDA批准的药物，具有可扩展的组件，允许在合成期间精确调整尺寸。本项目将测试“总体假设 **，即与有机结合碘（PEG-三碘）结合的聚乙二醇基赖氨酸树枝状聚合物是可行的MMCM，可用于在CT下获得大鼠模型中微血管渗漏和血浆体积分数的准确测量值。四个“具体目标”中的实验将：（1）确定由这类化合物合成一系列化学纯MMCM的简单性并评价其化学特性;（2）测定合成的MMCM的体内特性，包括用MMCM增强的动态CT的效应量，以量化血管渗漏响应于抗-VEGF抗体作为选择最佳化合物用于未来开发的手段;（3）确定用上述鉴定的最佳MMCM获得的动态CT扫描是否可以区分不同侵袭性的肿瘤;和（4）确定最佳化合物的大规模合成是否可行。在完成我们的研究后，我们最好的MMCM造影材料将具有评估动物肿瘤模型中微血管介导性变化的价值，并将提交给NIH资助的DCIDE项目进行正式的再临床毒理学评估，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.