February 2, 2021
A new, targeted RNA nanoparticle designed to carry a chemotherapy drug and to inhibit drug resistance 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).
This study, published in the Journal of Controlled Release, shows that the RNA nanoparticles efficiently target hepatocellular carcinoma (HCC) cells and are stable, safe and effective in laboratory and animal studies. The findings suggest that the nanoparticles could offer a new and effective treatment for HCC, the third-leading cause of cancer death worldwide.
The RNA nanoparticles display molecules that target HCC cells and carry molecules of the chemotherapy drug paclitaxel. They also contain a microRNA that inactivates a molecular pump called p-glycoprotein, which removes toxic chemicals from cells.
“Liver cancer cells overexpress drug exporter molecules and use them to remove chemotherapeutic drugs, which renders the drugs ineffective and contributes to drug resistance,” says study leader and corresponding author Peixuan Guo, PhD, professor in Ohio State’s College of Pharmacy and the Sylvan G. Frank Endowed Chair in Pharmaceutics and Drug Delivery. Guo also is in the Translational Therapeutics Program at the OSUCCC – James. “This could be why liver cancer responds poorly to chemotherapy treatment.”
Earlier work by Guo and his team showed that RNA nanoparticles have elastic and rubbery properties that enable them to stretch, shrink and return to their normal shape.
“We believe that this rubber-like property enables RNA nanoparticles to slip through the poorly formed walls of tumor blood vessels and enter a 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 relatively quickly,” Guo said. That, in turn, could reduce retention of an anticancer agent in vital organs, lowering its toxicity, he notes.
For this study, Guo and his colleagues constructed the RNA nanoparticles using six RNA strands that self-assemble into a globular structure. They conjugated 24 molecules of paclitaxel to these, along with three HCC targeting molecules (they are a derivative of galactosamine). The sequence for the microRNA – miR122 – extends from one of the RNA strands. The final structure is about 18 nanometers in size.
The study’s key findings include:
- Laboratory studies showed that the RNA nanoparticles selectively bind to, and were efficiently taken up by, an HCC cell line.
- The attached miR122 effectively inhibited drug-efflux pump proteins.
- RNA nanoparticles carrying both miR122 and paclitaxol most effectively inhibited tumor growth compared to paclitaxel or miR122 alone, and without affecting healthy organs; nanoparticles without treatment groups showed no cancer-cell inhibition effects.
- Animal studies showed that the RNA nanoparticle formulation targeted tumor cells effectively, and that miR122 and paclitaxel worked synergistically to strongly inhibit tumor growth.
“Overall,” Guo says, “our findings suggest that our rubber-like multivalent RNA nanoparticles could offer an effective treatment for liver cancer, a currently incurable, deadly disease.”
A grant from the National Institutes of Health (CA151648) supported this research.
Other researchers involved in this study were Hongzhi Wang, Satheesh Ellipilli, Wen-Jui Lee, Xin Li and Mario Vieweger, The Ohio State University; and Yuan-Soon Ho, Taipei Medical University, Taiwan.