Integrins are adhesion molecules associated with several hallmarks of malignant tumors including tumor invasion, formation of metastasis, tumor-induced angiogenesis and apoptosis of aberrant and activated endothelial cells. Expression in tumor cells of ava3integrin (ABIR) alters the interaction of cells with the extra-cellular matrix, and accelerates tumor growth and invasiveness. Due to involvement with these critical stages of tumor progression, integrins are attractive target for molecular level strategies aimed at imaging and treating pathogenesis. A common recognition motif for integrins is a structurally diverse tripeptide sequence, RGD (Arg-Gly-Asp). Analogues of RGD peptides (RGDPAs) provide an approach to target integrin expression. Highly sensitive, non-ionizing diffuse optical tomography methods can be used to image the distribution of target integrin in diseased tissue. Our preliminary data show that conjugating RGD-containing peptides to near infrared (NIR) fluorophores produces compounds that specifically target ABIR-positive tumors. Accordingly, we plan to (1) use computational methods to design, screen, select, and optimize 60 ABIR-avid NIR-RGDPAs; (2) develop method for synthesizing the peptides and their conjugates; (3) evaluate the ABIR binding affinity, internalization, cytotoxicity, proliferative effects, and subcellular distribution of NIR-RGDPAs in cells by in vitro assays; (4) develop and use a diffuse optical tomography system to evaluate the localization of candidate probes in vivo; and (5) evaluate the biodistribution of selected cypate-RGDPAs and optimize dosage for in vivo use with ex vivo fluorescence. The immediate goal for the first year is to assemble a highly sensitive DOT system, select bioactive NIR-RGDPAs by computational screening and initiate their synthesis. The long term goal is to develop a technology platform for rapid screening of bioactive molecules and for contrast-mediated molecular optical imaging of ABIR-positive diseases and neovasculature. At the completion of this project, we will (1) identify at least one ABIR-specific optical probe for translational research, (2) develop software for """"""""virtual screening"""""""" of putative bioactive ligands, and (3) develop a DOT system for longitudinal imaging of drug distribution in animals. All these products will be made available to other investigators.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA109754-05
Application #
7434395
Study Section
Special Emphasis Panel (ZRG1-MI (01))
Program Officer
Baker, Houston
Project Start
2004-09-21
Project End
2010-05-31
Budget Start
2008-06-01
Budget End
2010-05-31
Support Year
5
Fiscal Year
2008
Total Cost
$552,035
Indirect Cost
Name
Washington University
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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