Two studies led by researchers at The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James), USA, suggest that RNA nanoparticles may vastly improve the solubility, delivery and safety of two chemotherapeutic drugs.
In one study, researchers used RNA nanoparticles to deliver the chemotherapeutic drug paclitaxel, commonly used to treat breast as well as many other cancers; that study is published in the journal Nature Communications.
The second study used RNA nanoparticles that were engineered in a slightly different way to carry camptothecin in an animal model; the findings are reported in the journal Advanced Science.
Both studies were published by Pexiuan Guo, PhD, and colleagues with the OSUCCC – James Translational Therapeutics Research Program.
The team established proof-of-concept for RNA nanotechnology more than two decades ago, describing how nano-meter scale RNA structures are assembled, featured in Cell, opening a new pathway for research.
Both paclitaxel and camptothecin dissolve poorly in water, and are highly toxic, resulting in serious side effects.
Their toxicities are due in part to their low solubility, which requires that the two drugs be specifically formulated in a way that they are tolerable and safe to use in patients for cancer control.
Guo describes RNA nanotechnology as analogous to interconnecting building blocks like LEGOs.
To harness this approach to drug-delivery, RNA molecules are modified to, first, make them highly stable in water; second, carry a number of drug molecules; and third, display a molecule (i.e., an RNA aptamer) that targets a receptor on cancer cells.
“Our studies demonstrate the feasibility of using RNA nanoparticles to safely and efficiently deliver small-molecule chemotherapeutic drugs to tumour cells,” said Guo, who served as prinicipal investigator of the two studies and is a Professor of Pharmacy and the Sylvan G. Frank Endowed Chair in Pharmaceutics and Drug Delivery in the Ohio State University College of Medicine.
Guo also directs Ohio State’s Center for RNA Nanobiotechnology and Nanomedicine.
“In both studies, these therapeutic RNA nanoparticles were highly stable, had well-defined structure, and showed precise drug loading and targeted delivery,” said Guo.
Guo noted that, once inside tumour cells, the drug was released from the RNA nanoparticles and retained its ability to kill cancer cells and inhibit tumour growth.
Key findings of the paclitaxel study:
- The paclitaxel RNA nanoparticle was composed of a four-way junction structure and carried 24 paclitaxel prodrug molecules;
- Using RNA nanoparticles increased the water solubility of paclitaxel 32,000-fold;
- The paclitaxel RNA nanoparticles displayed an RNA aptamer (sequence-dependent RNA structure domain) that binds epidermal growth factor receptor (EGFR), which is often overexpressed on breast cancer cells;
- In a triple-negative breast-cancer animal model, the targeted RNA-paclitaxel nanoparticles dramatically inhibited breast cancer growth, with nearly undetectable toxicity and no fatalities.
- The therapeutic RNA nanoparticles efficiently target to tumour with little accumulation in vital organs.
Key findings of the camptothecin study:
- Each RNA nanoparticle was composed of a three-way junction structure that carried seven camptothecin prodrug molecules;
- Using RNA nanoparticles increased the water solubility of camptothecin 1,000-fold;
- The RNA nanoparticles displayed cancer binding ligands as a way to target tumour cells that overexpress the receptors on their surface.
“The display of EGFR binding RNA aptamer on the nanoparticles specifically recognised the overexpressed TNBC EGF receptors on the tumour cell surface and increased the uptake of the nanoparticles into tumour cells,” Guo explained.
“Collectively, our data demonstrates the feasibility of RNA nanoparticles for the safe and effective targeted delivery of hydrophobic anti-tumour drugs,” concluded Guo.