Posttranscriptional gene silencing by small interfering RNA (siRNA) has evolved into a powerful tool for down regulation of any target gene(s) with both high efficiency and sequence specificity. In principle, siRNA may become the basis for developing the next generation of antiviral and anti-cancer agents with high potencies and low side toxicities. However, no therapeutically acceptable delivery methods of siRNA are currently available. Although folate receptor (FR)-mediated delivery of functional agents by endocytosis to cancer cells has been shown to be efficient and highly specific towards FR-positive cancer cells, the chemistry of direct coupling between folate and siRNA has not been readily achievable until now. Capitalizing on the recent RNA bio-conjugation methods developed in the Huang (PI) laboratory, this proposed research will develop a novel folate receptor-based siRNA delivery strategy against specific target genes in FR-expressing cancer cells. Integrating the recent advances in such diverse areas as FR-mediated drug delivery and RNA interference (RNAi) with the expertise of the PI in chemistry/RNA and Dr. Quo (co-Pi) in cell biology, we will synthesize folate-conjugated siRNA and investigate their cellular delivery and functions, targeting a cancer cell marker, urokinase plasminogen activator receptor (uPAR). We will test the hypothesis that down- regulation uPAR expression in cancer cells by floate-conjugated siRNA will effectively inhibit the cellular activity of uPAR associated with tumor growth. Both the delivery efficiency and specificity of Folate-siRNA will be analyzed using KB cancer cells (a human nasopharyngeal epidermoid carcinoma cell line). RNAi effects will be assessed by determining the expression of uPAR at mRNA and protein levels and by cellular functional analysis of uPAR. We expect that the delivery of Folate-siRNA against uPAR in KB cells will be more efficient and specific than other current available methods. As a consequence, tumor growth suppression through uPAR silencing is expected. Results from the proposed research will likely lead to the development of general strategies and methods for FR-mediated delivery of siRNA against specific target genes in FR-expressing cancer cells and, therefore, may lead directly to cancer therapeutic applications.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
3R21CA120566-02S1
Application #
7911247
Study Section
Special Emphasis Panel (ZCA1-SRRB-K (O1))
Program Officer
Couch, Jennifer A
Project Start
2009-08-01
Project End
2010-07-31
Budget Start
2009-08-01
Budget End
2010-07-31
Support Year
2
Fiscal Year
2009
Total Cost
$120,684
Indirect Cost
Name
University of Southern Mississippi
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
623335775
City
Hattiesburg
State
MS
Country
United States
Zip Code
39406