The peptide-siRNA nanoparticle technology applied in the preclinical study was developed by USF Health Heart Institute researchers

Advanced ovarian and uterine cancers are deadly diseases. Ovarian cancers, in particular, present with vague symptoms common to other diseases, and often are not diagnosed until a late stage when cancer has spread throughout the abdomen.  More options are needed to effectively treat these metastasized gynecological cancers and improve patient survival rates.

A preclinical study published recently in Scientific Reports demonstrates that nanoparticle-delivered small interfering RNA (siRNA) targeting production of the protein AXL (AXL siRNA) inhibits metastasis of ovarian and uterine cancer cells.  The study was conducted by researchers at Washington University School of Medicine, St. Louis, Mo., and the USF Health Heart Institute, University of South Florida Morsani College of Medicine, Tampa, Fla.

3D illustration of ovarian cancer

The research team used a new nanoparticle system developed by USF Health co-investigators Samuel Wickline, MD, and Hua Pan, MBA, PhD, to test the experimental nanotherapy in human uterine and ovarian tumor cells and in immunodeficient mice implanted with these cancer cells.

“We’ve figured how to package in a simple peptide all the critical steps needed to efficiently get this particular small interfering RNA (also known as silencing RNA) into tumor cells and then release the siRNA so it can do its job,” said Dr. Wickline, a professor of cardiovascular sciences who direct the USF Health Heart Institute. “The nanoparticle basically hijacks the tumor cells’ biological machinery to get the siRNA where it needs to go – without being destroyed along the way, or creating harmful side effects.”

The nanoparticle combines two components in one delivery package 100 times smaller than a red blood cell: AXL siRNA and the peptide p5RHH.  AXL siRNA is designed to target and silence the expression of AXL, a key molecule that drives uterine and ovarian cancers. The p5RHH nanoparticles are derived from a major substance of bee venom called melittin, detoxified and selectively modified to facilitate timely escape of AXL siRNA from the nanostructure once the silencing RNA is delivered inside the targeted tumor cells.

Among the findings of the Washington University-USF Health study:

• In cell culture, treatment with p5RHH-siAXL nanoparticles decreased the ability of uterine and ovarian cancer cells to migrate and invade neighboring normal tissues.
• Mice with established uterine and ovarian tumors were intravenously and abdominally (intraperitoneally) injected with nanoparticles containing p5RHH and fluorescent control siRNA. The peptide nanoparticles localized to and released their contents into both tumor cell types regardless of the injection route, but fluorescent imaging showed that intraperitoneal administration was more effective than IV administration.
• In the mouse models, p5RHH-siALX treatment significantly reduced metastasis of both uterine and ovarian cancer without toxic effects.

USF Health Heart Institute Director Samuel Wickline, MD, and biomedical engineer Hua Pan, PhD, build nanoparticles to safely and efficiently deliver drugs or other therapeutic agents to specific cell types.

Overall, the study demonstrates this nanoparticle approach shows promise for treating patients with ovarian or uterine cancers, the authors conclude.

Challenges in translating preclinical successes into patient care remain, but Dr. Wickline believes nanoparticle-mediated delivery of siRNA has applications beyond just suppressing one target (AXL) implicated in other cancers in addition to uterine and ovarian.

The power of harnessing tiny nanotechnology for gene therapies lies in its flexibility, he said.

“As we identify new disease-modifying targets, it offers the potential to attack multiple different targets at the same time.  So, one nanoparticle could deliver a whole host of genetic materials – a combination of RNA interference drugs, or other types of synthetic RNA or DNA-based drugs —  to hit any specific cell types where treatment is needed.”