This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The objective of this proposal is to develop cross-linked core polyion nanocarrier (PNC) for the targeted systemic delivery of siRNA to activated microvascular endothelial cells (MVEC) to attenuate tumor angiogenesis and subsequent tumor growth. We posit that 1) the binding selectivity of siRNA-loaded PNCs for the surface of activated MVEC can be increased against untargeted cells of the vascular compartment;(2) targeted PNC-siRNA will efficiently internalize and release siRNA within activated MVEC;and 3) increasing intracellular delivery of siRNA with PNCs targeted for the surface of activated MVEC will increase siRNA activities against tumor angiogenesis and subsequent tumor growth. A vascular cell-restricted protein required for angiogenesis, p73RhoGAP, will be targeted by siRNA. The hypotheses will be tested using mouse dermal MVEC in vitro and a mouse model of melanoma in vivo. First, PNC structure and targeting ligand modifications that maximize the binding selectivity of PNC-siRNA for the surface of activated MVEC and intracellular siRNA release will be established. Second, the efficacy of targeted PNC-siRNA against MVEC proliferation and migration will be determined in vitro. Third, the biodistribution and efficacy of targeted PNC-siRNA against tumor vascular function and tumor growth will be determined in vivo. If successful this work will lead to more efficient anti-angiogenesis treatments of cancer.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Exploratory Grants (P20)
Project #
5P20RR021937-04
Application #
8360239
Study Section
Special Emphasis Panel (ZRR1-RI-2 (01))
Project Start
2011-07-01
Project End
2012-06-30
Budget Start
2011-07-01
Budget End
2012-06-30
Support Year
4
Fiscal Year
2011
Total Cost
$223,081
Indirect Cost
Name
University of Nebraska Medical Center
Department
Other Basic Sciences
Type
Schools of Pharmacy
DUNS #
168559177
City
Omaha
State
NE
Country
United States
Zip Code
68198
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