Our research is focused on the potential of acid-prepared mesoporous silica (APMS) as a delivery agent for siRNA constructs to inhibit the ERK1/2 and ERK5 pathways in the treatment of human malignant mesothelioma (MM). These pathways are critical to MM cell proliferation and chemoresistance. Our initial research suggests that APMS will be significantly more effective as a vehicle for uptake and delivery of siRNA constructs into the thoracic cavity than current alternatives. Prior research shows that modified APMS effectively transfers DNA plasmids to epithelial and mesothelioma cells in vitro. APMS itself is not toxic to cells in vitro or after injection intranasally or intrathoracically into mice. The external surface of APMS can be modified for cell specific targeting and maximal uptake. The proposed research as three main goals: (1) engineer APMS for maximum and selective uptake by human MM cells in vitro; (2) study the kinetics of uptake of shRNA constructs into APMS; and (3) use shRNA-loaded APMS to block ERK1/2 and ERK5 pathways. Assuming the Phase I in vitro research validates our hypothesis that shRNA-loaded APMS both improves the uptake of the constructs to MM cells and significantly increases the interference of the constructs with the ERK1/2 and ERK5 pathways, our Phase II research will involve the in vitro functional effects of shRNA-loaded constructs in human MM and in vivo work with a mouse xenograft model. In addition, we plan to expand our research to other shRNA constructs that block other signaling pathways. Since a universal obstacle to all siRNA therapeutics is the delivery of the molecules into the cells, APMS offers the potential of revolutionizing the clinical opportunity for siRNA. Our primary focus is on the cancer drug market, a $36.9B in 2004. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Small Business Technology Transfer (STTR) Grants - Phase I (R41)
Project #
5R41CA126155-02
Application #
7499710
Study Section
Special Emphasis Panel (ZRG1-BST-Z (10))
Program Officer
Kurtz, Andrew J
Project Start
2007-09-24
Project End
2010-07-31
Budget Start
2008-08-01
Budget End
2010-07-31
Support Year
2
Fiscal Year
2008
Total Cost
$100,000
Indirect Cost
Name
Apollo Sri, LLC
Department
Type
DUNS #
143736614
City
Burlington
State
VT
Country
United States
Zip Code
05405
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Macura, Sherrill L; Steinbacher, Jeremy L; Macpherson, Maximilian B et al. (2013) Microspheres targeted with a mesothelin antibody and loaded with doxorubicin reduce tumor volume of human mesotheliomas in xenografts. BMC Cancer 13:400
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