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. ? ? ?
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