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.
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.
|Murmann, Andrea E; Gao, Quan Q; Putzbach, William E et al. (2018) Small interfering RNAs based on huntingtin trinucleotide repeats are highly toxic to cancer cells. EMBO Rep 19:|
|Bell, Jonathan B; Rink, Jonathan S; Eckerdt, Frank et al. (2018) HDL nanoparticles targeting sonic hedgehog subtype medulloblastoma. Sci Rep 8:1211|
|Plebanek, Michael P; Bhaumik, Debayan; Bryce, Paul J et al. (2018) Scavenger Receptor Type B1 and Lipoprotein Nanoparticle Inhibit Myeloid-Derived Suppressor Cells. Mol Cancer Ther 17:686-697|
|Rink, Jonathan S; Yang, Shuo; Cen, Osman et al. (2017) Rational Targeting of Cellular Cholesterol in Diffuse Large B-Cell Lymphoma (DLBCL) Enabled by Functional Lipoprotein Nanoparticles: A Therapeutic Strategy Dependent on Cell of Origin. Mol Pharm 14:4042-4051|
|Plebanek, Michael P; Angeloni, Nicholas L; Vinokour, Elena et al. (2017) Pre-metastatic cancer exosomes induce immune surveillance by patrolling monocytes at the metastatic niche. Nat Commun 8:1319|
|McMahon, Kaylin M; Scielzo, Cristina; Angeloni, Nicholas L et al. (2017) Synthetic high-density lipoproteins as targeted monotherapy for chronic lymphocytic leukemia. Oncotarget 8:11219-11227|
|Murmann, Andrea E; McMahon, Kaylin M; Haluck-Kangas, Ashley et al. (2017) Induction of DISE in ovarian cancer cells in vivo. Oncotarget 8:84643-84658|
|Mutharasan, R Kannan; Foit, Linda; Thaxton, C Shad (2016) High-Density Lipoproteins for Therapeutic Delivery Systems. J Mater Chem B 4:188-197|
|Thaxton, C Shad; Rink, Jonathan S; Naha, Pratap C et al. (2016) Lipoproteins and lipoprotein mimetics for imaging and drug delivery. Adv Drug Deliv Rev 106:116-131|
|Angeloni, Nicholas L; McMahon, Kaylin M; Swaminathan, Suchitra et al. (2016) Pathways for Modulating Exosome Lipids Identified By High-Density Lipoprotein-Like Nanoparticle Binding to Scavenger Receptor Type B-1. Sci Rep 6:22915|
Showing the most recent 10 out of 25 publications