We aim to develop a targeted nanoparticle-based cancer therapy. We chose advanced prostate cancer (PCa) because androgen deprivation therapy (ADT), the only effective therapeutic option, fails after a relatively brief initial respone. Because of its high mortality rate, and significant impact on patient quality of life, novel treatment modalities for advanced PCa are highly important and much needed. The failure of anti-androgens is due, at least in part, to autonomous local testosterone production by PCa tumor cells. As a result, advanced PCa develops a unique requirement for cholesterol, which is a substrate for androgen biosynthesis. Cholesterol, insoluble in aqueous solution, is internalized via lipoproteins, specifically high density lipoproteins (HDL) in PCa. HDL and cholesterol uptake occur through the HDL uptake receptor, scavenger receptor B-1 (SR-B1), which is up-regulated in advanced PCa. We will employ the increased SR-B1 expression for PCa targeting with nanoconjugates to deliver gene targeted siRNA. We hypothesize that efficient systemic delivery of nucleic acid cargo can be facilitated by the robust and directed fabrication of biomimetic spherical HDL nanoparticles using a novel approach pioneered by our group. Recently, our group utilized a gold nanoparticle scaffold (AuNP) to generate biomimetic HDLs that recapitulate the size, shape, surface chemistry, and cholesterol binding properties of mature spherical HDLs. The resulting nanoparticles (HDL AuNPs) adsorb nucleic acids with high affinity. Initial in vitro and in vivo experiments show that these unique biomaterials are non-toxic, accumulate in the tissues that normally bind HDL, and function to regulate target gene expression. We propose to characterize and optimize the HDL AuNP conjugates loaded with siRNA and to test their properties in vitro and in preclinical model of prostate cancer. We expect that HDL AuNPs carrying siRNA will accumulate in the sites of SR-B1 expression, including in experimental PCa where SR-B1 is over-expressed, and efficiently deliver siRNA to PCa cells. Thus delivered, siRNA will block the expression of target gene(s). As a model target we chose the androgen receptor, a critical mediator of advanced prostate cancer. Project success will result in an effective and targeted siRNA therapy for advanced prostate cancer.

Public Health Relevance

This multidisciplinary proposal uniquely addresses the need for effective therapies to combat advanced prostate cancer. Advanced prostate cancer becomes dependent upon cholesterol uptake through high density lipoproteins (HDL) for progression. By using a biomimetic nanostructure of high density lipoprotein (HDL), this proposal leverages the biological need for cholesterol to develop a potent and targeted method of systemic therapeutic nucleic acid delivery to prostate cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA167041-02
Application #
8549175
Study Section
Developmental Therapeutics Study Section (DT)
Program Officer
Fu, Yali
Project Start
2012-09-21
Project End
2017-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
2
Fiscal Year
2013
Total Cost
$301,353
Indirect Cost
$106,303
Name
Northwestern University at Chicago
Department
Urology
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
McMahon, Kaylin Marie; Thaxton, Colby Shad (2014) High-density lipoproteins for the systemic delivery of short interfering RNA. Expert Opin Drug Deliv 11:231-47
Tripathy, Sushant; Vinokour, Elena; McMahon, Kaylin M et al. (2014) High Density Lipoprotein Nanoparticles Deliver RNAi to Endothelial Cells to Inhibit Angiogenesis. Part Part Syst Charact 31:1141-1150
Rink, Jonathan S; Plebanek, Michael P; Tripathy, Sushant et al. (2013) Update on current and potential nanoparticle cancer therapies. Curr Opin Oncol 25:646-51