Integrins are heterodimeric transmembrane receptors that mediate the interactions between endothelial cells and the extracellular matrix. They are involved in a large number of fundamental intracellular processes, such as cell-matrix adhesion, differentiation, stress response and apoptosis. Among the integrins, ?v?3 receptors are overexpressed in endothelial cells undergoing angiogenesis, although they are not typically found on quiescent cells. This renders them attractive antitumor targets, since antagonists of this receptor that effectively compete with its natural ligands cause apoptosis in proliferating vessels. The objective of our study is to examine the efficacy of multivalent modular dendritic integrin antagonists (MDIA) as tools in cancer imaging, in boron neutron capture therapy (BNCT) and as inhibitors of angiogenesis. In particular, modular constructs incorporating multiple integrin recognition domains might show increased affinity and specificity for angiogenic endothelial cells. In addition to acting as agents for imaging of neovasculature, such multivalent species might be capable of interfering with the endocytic cycle of ?v?3 integrins or the angiogenic process itself. Angiogenesis, the process of formation of new blood vessels as sprouts of the existing vasculature, is critical for growth and metastatic spread of solid tumors. Our project aims to uncover new chemical approach for selective recognition of cell surface receptors - integrins that are overexpressed on the surface of endothelial cells undergoing angiogenesis. The new class of designed multivalent integrin ligands may allow cells or tissues to be targeted based on distinct receptor expression patterns and blocking angiogenesis without affecting normal blood vessel cells. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21CA129388-02
Application #
7456507
Study Section
Drug Discovery and Molecular Pharmacology Study Section (DMP)
Program Officer
Lees, Robert G
Project Start
2007-07-01
Project End
2010-06-30
Budget Start
2008-07-01
Budget End
2010-06-30
Support Year
2
Fiscal Year
2008
Total Cost
$117,752
Indirect Cost
Name
University of Arizona
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
806345617
City
Tucson
State
AZ
Country
United States
Zip Code
85721
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Xu, Shi; Olenyuk, Bogdan Z; Okamoto, Curtis T et al. (2013) Targeting receptor-mediated endocytotic pathways with nanoparticles: rationale and advances. Adv Drug Deliv Rev 65:121-38
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