Overexpression of alpha(v)beta(3) integrin on the surfaces of tumor cells and activated endothelial cells as compared to normal cells and rest endothelial cells implicates the application of radiolabeled alpha(v)beta(3) integrin antagonist for imaging of alpha(v)beta(3) expression levels in alpha(v)beta(3) positive tumors. The goal of this proposal is to develop copper-64 (t1/2 = 12.7 h) labeled RGD peptide antagonists of alpha(v)beta(3) integrin for breast cancer targeting by means of positron emission tomography (PET). We hypothesize that conjugation and radiolabeling of RGD peptides will have significant effect on the receptor binding affinity and specificity, as well as the in vivo pharmacokinetics of these radiotracers. To make the tracers clinically applicable for patient segmentation based upon alpha(v)beta(3) integrin expression levels, systematic studies have to be performed to optimize the tracer in such a way that the tracer will have fast and high yield radiolabeling, in vivo stability against transchelation, and high receptor binding affinity and specificity. The radiotracer should also be designed to have satisfactory in vivo pharmacokinetics for high quality imaging: high tumor-to-normal tissue ratio, fast circulation clearance, low kidney uptake and fast renal clearance, as well as avoiding hepatobiliary excretion. The research proposed here is to: 1) develop and optimize copper-64 labeled RGD peptides for breast cancer tumor targeting; and 2) correlate the magnitude of tumor uptake with tumor integrin density levels in preclinical animal models. The success of this research will facilitate the rapid translation of this laboratory work into clinical applications, since the features of small animal PET imaging studies closely reflect the settings of a clinical PET study for human beings. We anticipate that noninvasive serial studies of alpha(v)beta(3) expression and functional activity using PET will become an important tool to evaluate the role of alpha(v)beta(3) integrin during tumor progression and metastasis.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21CA102123-01A2
Application #
6982870
Study Section
Medical Imaging Study Section (MEDI)
Program Officer
Croft, Barbara
Project Start
2005-09-30
Project End
2007-08-31
Budget Start
2005-09-30
Budget End
2006-08-31
Support Year
1
Fiscal Year
2005
Total Cost
$201,328
Indirect Cost
Name
Stanford University
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Liu, Zhaofei; Liu, Shuanglong; Niu, Gang et al. (2010) Optical imaging of integrin alphavbeta3 expression with near-infrared fluorescent RGD dimer with tetra(ethylene glycol) linkers. Mol Imaging 9:21-9
Niu, Gang; Sun, Xilin; Cao, Qizhen et al. (2010) Cetuximab-based immunotherapy and radioimmunotherapy of head and neck squamous cell carcinoma. Clin Cancer Res 16:2095-105
Li, Zi-Bo; Chen, Kai; Wu, Zhanhong et al. (2009) 64Cu-labeled PEGylated polyethylenimine for cell trafficking and tumor imaging. Mol Imaging Biol 11:415-23
Liu, Zhaofei; Yan, Yongjun; Chin, Frederic T et al. (2009) Dual integrin and gastrin-releasing peptide receptor targeted tumor imaging using 18F-labeled PEGylated RGD-bombesin heterodimer 18F-FB-PEG3-Glu-RGD-BBN. J Med Chem 52:425-32
Chen, Kai; Cai, Weibo; Li, Zi-Bo et al. (2009) Quantitative PET imaging of VEGF receptor expression. Mol Imaging Biol 11:15-22
Liu, Zhaofei; Li, Zi-Bo; Cao, Qizhen et al. (2009) Small-animal PET of tumors with (64)Cu-labeled RGD-bombesin heterodimer. J Nucl Med 50:1168-77
Liu, Zhaofei; Liu, Shuanglong; Wang, Fan et al. (2009) Noninvasive imaging of tumor integrin expression using (18)F-labeled RGD dimer peptide with PEG (4) linkers. Eur J Nucl Med Mol Imaging 36:1296-307
Niu, Gang; Li, Zibo; Xie, Jin et al. (2009) PET of EGFR antibody distribution in head and neck squamous cell carcinoma models. J Nucl Med 50:1116-23
Li, Zi-Bo; Chen, Xiaoyuan (2009) MicroPET, MicroSPECT, and NIR fluorescence imaging of biomolecules in vivo. Methods Mol Biol 544:461-81
Niu, Gang; Chen, Xiaoyuan (2009) PET Imaging of Angiogenesis. PET Clin 4:17-38

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