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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA122257-04
Application #
7808842
Study Section
Medical Imaging Study Section (MEDI)
Program Officer
Zhang, Yantian
Project Start
2007-08-01
Project End
2012-05-31
Budget Start
2010-06-01
Budget End
2012-05-31
Support Year
4
Fiscal Year
2010
Total Cost
$451,578
Indirect Cost
Name
University of California San Francisco
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Rathnayake, Samira; Mongan, John; Torres, Andrew S et al. (2016) In vivo comparison of tantalum, tungsten, and bismuth enteric contrast agents to complement intravenous iodine for double-contrast dual-energy CT of the bowel. Contrast Media Mol Imaging 11:254-61
Mongan, John; Rathnayake, Samira; Fu, Yanjun et al. (2013) Extravasated contrast material in penetrating abdominopelvic trauma: dual-contrast dual-energy CT for improved diagnosis--preliminary results in an animal model. Radiology 268:738-42
Varenika, Vanja; Fu, Yanjun; Maher, Jacquelyn J et al. (2013) Hepatic fibrosis: evaluation with semiquantitative contrast-enhanced CT. Radiology 266:151-8
Mongan, John; Rathnayake, Samira; Fu, Yanjun et al. (2012) In vivo differentiation of complementary contrast media at dual-energy CT. Radiology 265:267-72
Wang, Zhen J; Chen, Katherine S; Gould, Robert et al. (2011) Positive enteric contrast material for abdominal and pelvic CT with automatic exposure control: what is the effect on patient radiation exposure? Eur J Radiol 79:e58-62
Yeh, Benjamin M (2011) Abdominal CT at low peak tube potential settings brings promises, but new rules apply. AJR Am J Roentgenol 196:1322-3
Chou, Shinn-Huey; Wang, Zhen J; Kuo, Jonathan et al. (2011) Persistent renal enhancement after intra-arterial versus intravenous iodixanol administration. Eur J Radiol 80:378-86
Kumar, Rahi; Wang, Zhen J; Fu, Yanjun et al. (2010) Visualization of renal medullary hyperattenuation at unenhanced CT: what is the effect of furosemide administration? Radiology 255:495-500
Raatschen, Hans-Juergen; Fu, Yanjun; Brasch, Robert C et al. (2009) In vivo monitoring of angiogenesis inhibitory treatment effects by dynamic contrast-enhanced computed tomography in a xenograft tumor model. Invest Radiol 44:265-70
Benedetti, Nancy; Aslam, Rizwan; Wang, Zhen J et al. (2009) Delayed enhancement of ascites after i.v. contrast material administration at CT: time course and clinical correlation. AJR Am J Roentgenol 193:732-7

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