A new targeted RNA nanoparticle designed to carry a chemotherapy drug along with a therapeutic oligonucleotide against chemical efflux gene might provide an effective treatment for liver cancer, according to a new study led by researchers at The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James).

The study, published in the Journal of Controlled Release, shows that the RNA nanoparticles efficiently target hepatocellular carcinoma (HCC, one kind of liver cancer) cells and are stable, safe, and effective both in laboratory and animal studies. The findings suggest that the nanoparticles could offer an effective new treatment for HCC. 

The RNA nanoparticles carry a chemotherapeutic drug, Paclitaxel, and display molecules that target HCC cells. They also contain a microRNA that inactivates a chemical efflux pump called p-glycoprotein, which usually pumps out chemotherapeutic drugs from the liver cells, making cancer untreatable.

The liver can be regarded as the body’s checkpoint for blocking and removing toxins from the body. In the body, for most chemicals or drugs, no matter they were intravenously injected or absorbed through intestines, their first step station is the liver.   

“Liver cells express drug exporter pumps that are used to remove chemotherapeutic drugs and detoxify the body. This renders the treatment with chemical drugs ineffective,  and contributes to drug resistance,” says study leader and corresponding author Peixuan Guo, PhD, professor at Ohio State’s College of Pharmacy and the Sylvan G. Frank Endowed Chair in Pharmaceutics and Drug Delivery. Guo also is a member of the OSUCCC - James Translational Therapeutics Program. “This could be why liver cancer responds poorly to chemotherapy treatment.”

Earlier work by Guo and his team showed that RNA nanoparticles have rubbery or amoeba-like properties that enable them to stretch, shrink then return to their normal shape.

“We believe that this amoeba and rubber-like property enables RNA nanoparticles to slip through the poorly formed walls of tumor blood vessels and enter the tumor mass,” said Guo, who directs Ohio State’s Center for RNA Nanobiotechnology and Nanomedicine. 

“This same rubbery property could allow the kidneys to filter RNA nanoparticles from the blood and excrete them in the urine, thereby eliminating them from the body swiftly,” Guo said. “This, in turn, could reduce retention of anticancer RNA nanoparticles in vital organs, lowering the drug’s toxicity.”

For this study, Guo and his colleagues constructed the RNA nanoparticles using six RNA strands that self-assembled into a globular structure. The nanoparticle served as a cargo system to deliver both Paclitaxel and microRNA (miR122) along with HCC targeting ligands. They conjugated 24 molecules of paclitaxel, along with HCC targeting molecules (a derivative of galactosamine) and one microRNA to the multivalent RNA nanoparticle. The sequence for the microRNA extends from one of the RNA strands. The final structure is about 18 nanometers in size.

The study’s key findings include:

• RNA nanoparticles selectively bind and deliver therapeutic agents into liver cancer cells efficiently.

• The attached miR122 effectively inhibits the liver drug-efflux pump.

• RNA nanoparticles carrying both Paclitaxel and miR122 more effectively inhibited tumor growth compared to Paclitaxel or miR122 alone; nanoparticles without treatment groups showed no cancer-cell inhibition effects.

• Animal studies showed that the RNA nanoparticle formulation targeted tumor cells effectively and strongly inhibited tumor growth due to the synergistic effect of Paclitaxel and miR122, without affecting healthy organs.

“Overall,” said Guo, “our findings suggest that the rubber-like multivalent RNA nanoparticles could offer an effective treatment for liver cancer, currently an incurable, deadly disease.”

This research was funded by the National Institutes of Health (CA151648).

Collaborators in this study are: Hongzhi Wang, Satheesh Ellipilli, Xin Li and Mario Vieweger of The Ohio State University; and Wen-Jui Lee and Yuan-Soon Ho, Taipei Medical University, Taiwan.

About the OSUCCC – James:

The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute strives to create a cancer-free world by integrating scientific research with excellence in education and patient-centered care, a strategy that leads to better methods of prevention, detection and treatment. Ohio State is one of 51 National Cancer Institute (NCI)-designated Comprehensive Cancer Centers and one of only a few centers funded by the NCI to conduct both phase I and phase II clinical trials on novel anticancer drugs sponsored by the NCI. As the cancer program’s 356-bed adult patient-care component, The James is one of the top cancer hospitals in the nation as ranked by U.S. News & World Report and has achieved Magnet® designation, the highest honor an organization can receive for quality patient care and professional nursing practice. With 21 floors and more than 1.1 million square feet, The James is a transformational facility that fosters collaboration and integration of cancer research and clinical cancer care.