Application of Nanotechnology to Novel Models of Prostate Cancer—Nanoscale Fabrication Technology May Provide New Modeling Capabilities and Therapies to Arrest Lethal PCa Progression

Co-Investigator: Shelton Earp, MD– Director and Lineberger Professor, Professor of Medicine and Pharmacology, Lineberger Comprehensive Cancer Center, University of North Carolina-Chapel Hill

Co-Investigator: Joseph DeSimone, PhD–Chancellor’s Eminent Professor of Chemistry, University of North Carolina-Chapel Hill, William R. Kenan, Jr. Distinguished Professor of Chemical Engineering, North Carolina State University

This program has discovered that a molecule named Ack1 can cause poorly-tumorigenic prostate cancer cells to become highly lethal. In addition, it has developed an innovative nanoparticle drug delivery technology using the same stepped layering and etch process used in the fabrication of today’s nanoscale semiconductors and microprocessors. The nanotherapy involves delivery of drugs in nanoscale discs that look like hockey pucks and are flexible like red blood cells as they circulate through capillaries. Inhibitors of Ack1 will be delivered to novel models of prostate cancer to credential the Ack1 target for discovery of new therapies for prostate cancer. Ultimately, it is hoped that Ack1 inhibitors delivered by flexile nanodiscs would be able to shut down the lethal progression of prostate cancer cells.

Progress Report:

The goal of this project was to develop nanoparticles that deliver novel cancer medicines specifically to prostate tumors. Nanoparticles are very small objects (the size of a virus) that are being developed as drug delivery vehicles. Dr. DeSimone has developed two distinct nanoparticle compositions that are generally safe and can therefore be used to treat patients by intravenous injection. The particles are decorated with molecules that target prostate cancer cells and not healthy cells. The biology team led by Dr. Earp loaded these targeted nanoparticles with two different cancer medicines, docetaxel (a chemotherapy medicine) and siRNAs (small interfering RNA: molecules that can silence cancer-causing genes), a fragile biologic cargo. Data reported in their progress report shows that nanoparticles containing docetaxel were much more effective at killing cancer cells than treatment with docetaxel alone. The nanoparticles were able to deliver 40% total weight of docetaxel, which is 16 times greater than any other reported nanoparticle drug delivery vehicle. A proof-of-concept was reported showing that nanoparticles could encapsulate siRNA that could be successfully released into cancer cells. The use of siRNAs in cancer therapy is a major goal because these molecules can inhibit currently “undruggable” targets with precise selectivity. The team is currently working on delivering an siRNA specific to Ack1 to prostate cancer cells. Ack1 is a gene hypothesized to play a critical role in prostate cancer initiation, progression and recurrence because of its integral role in androgenreceptor signaling, a central prostate cancer survival pathway. Early data shows that Ack1 is activated in human prostate cancers and that it may directly enhance the activity of androgen receptor. The advancements made in this creativity award project open up new strategies for treating advanced prostate cancer through the design of new mechanisms to deliver novel medicines directly to prostate cancer cells.