A recent study reveals that attaching antibody-like RNA nanoparticles to microvesicles can provide effective RNA therapeutics such as small interfering RNA (siRNA) precisely to cancer cells.
Researchers employ RNA nanotechnology to apply the RNA nanoparticles and manipulate their orientation to create microscopic, therapy-loaded extracellular vesicles that effectively targeted three types of cancer in animal models.
The findings, published in the Nature Nanotechnology journal, could pave the way towards a new generation of anticancer drugs that use microRNA, siRNA, and other RNA-interference technologies.
The study was guided by researchers at Ohio State’s College of Pharmacy and at the Ohio State University Comprehensive Cancer Center – James Cancer Hospital and Solove Research Institute (OSUCCC – James).
“Therapies that use siRNA and RNA interference technologies are poised to transform cancer therapy,” says the chief investigator Peixuan Guo, PhD, Sylvan G. Frank Endowed Chair professor of the College of Pharmacy and a member of the OSUCCC – James Translational Therapeutics Program. “But clinical trials evaluating these agents have failed one after another due to the inability to deliver the agents directly to cancer cells in the human body.”
Guo noted that even when agents did reach and go into cancer cells, they were trapped in internal vesicles known as endosomes and rendered unproductive.
Our findings solve two major problems that impede these promising anticancer treatments: targeted delivery of the vesicles to tumor cells and freeing the therapeutic from the endosome traps after it is taken up by cancer cells. In this study, cancers stopped growing after systemic injection of these particles into animal models with tumors derived from human patients. We’re working now to translate this technology into clinical applications.
Peixuan Guo, PhD, Chief Investigator
Guo and his colleagues created extracellular microvesicles that exhibit antibody-like RNA molecules known as aptamers that bind with a surface marker that is overexpressed by each of three tumor types:
- To impede prostate cancer, vesicles were engineered to bind to prostate-specific membrane antigen (PSMA);
- To impede a colorectal-cancer graft of human origin, vesicles were engineered to bind to folate receptors;
- To impede breast cancer, vesicles were engineered to bind to epidermal growth factor receptor (EGFR).
All vesicles were filled with a small interfering RNA for down regulating the survivin gene as a test therapy. The survivin gene impedes apoptosis and is overexpressed in a number of cancer types.
Main findings include:
- Vesicles targeting the prostate-specific membrane antigen totally impeded prostate-cancer growth in an animal model with no noticeable toxicity.
- Vesicles targeting EGFR impeded breast-cancer growth in an animal model.
- Vesicles targeting folate receptors greatly inhibited tumor growth of human patient-derived colorectal cancer in an animal model.
Overall, our study suggests that RNA nanotechnology can be used to program natural extracellular vesicles for delivery of interfering RNAs specifically to cancer cells.
Peixuan Guo, PhD, Chief Investigator
This research was financially supported by the National Institutes of Health/National Cancer Institute.
The study’s other researchers include Fengmei Pi, Daniel W. Binzel, Zhefeng Li, Hui Li, Farzin Haque, Shaoying Wang and Carlo M. Croce, The Ohio State University Wexner Medical Center; Meiyan Sun and Bin Guo, University of Houston; Piotr Rychahou and B. Mark Evers, University of Kentucky; and Tae Jin Lee, now at University of Texas.