Due to the findings of two different research studies completed by my team at The Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC - James), there is now evidence showing that modified RNA nanoparticles may vastly improve the solubility, delivery, and safety of two important chemotherapeutic drugs-a breakthrough in cancer treatment.
RNA nanotechnology is an exciting and emerging drug delivery platform that will change the way we administer drugs in the human body. To study RNA technology, interdisciplinary approaches including chemistry, biophysics, biochemistry, nanotechnology, bioengineering, molecular biology, cell biology, computer modeling, and pharmaceutical sciences were applied to observe their interactions.
The RNA Journey
I often refer to RNA nanoparticles as interconnecting building blocks-like LEGO bricks. To harness a new approach to drug delivery, RNA molecules are modified to make them suitable for broad applications. They have been modified to be highly stable in water and in vivo, carry a number of drug molecules, and display a molecule (an RNA aptamer, for example) that targets a receptor on cancer cells.
I was working with RNA molecules as early as 1986, when I found that cells have many small RNA molecules with undiscovered functions (Science 1987;236:690-694) in addition to the reported mRNA, rRNA, tRNA, ribozyme RNA, and URNA. I named them small RNA or "sRNA" for short. In 1998, I showed that RNA dimer, trimer, tetramer, and hexamer can be constructed by a bottom-up approach using engineered RNA, which helped prove the concept of RNA nanotechnology (Mol Cell 1998;2:149-155; featured in Cell).
In 2004, I predicted that RNA would be the third milestone in drug development. With the recent approval of three RNA-based drugs by the FDA, I believe this third milestone is coming.
The RNA nanoparticles we work with now are homogeneous in size and structure, thermodynamically and chemically stable, and display favorable pharmacological profiles with undetected toxicity and side effects. Their immunogenicity is shape-, size-, and sequence-dependent. That is, the RNA nanoparticles can be designed with little or undetected immune response to serve as a drug carrier or strong immune response to serve as a vaccine adjuvant or cancer immune therapy.
When injected, the rubbery property of RNA nanoparticles enables them to target a tumor quickly and efficiently. The majority of the rest of untargeted sRNA nanoparticles appear in urine and quickly clear from the body with little accumulation in healthy organs. The quick clearance makes RNA nanoparticles relatively safe for in vivo application.
RNA Research
At the OSUCCC - James, our research has shown the expanded utility of RNA nanoparticles in two different studies that showcase the nanoparticles' ability to improve the effectiveness of chemotherapeutic drugs paclitaxel and camptothecin. Both studies were published earlier this year in conjunction with my colleagues with the OSUCCC - James Translational Therapeutics Research Program.
Both paclitaxel and camptothecin dissolve poorly in water and are highly toxic, meaning the use of either can result in serious side effects for patients who are already facing a variety of challenges. They are both used to combat a variety of cancers, and paclitaxel is particularly known for its use in treating breast cancer.
These 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.
This pair of studies has demonstrated the feasibility of using RNA nanoparticles to safely and efficiently deliver small-molecule chemotherapeutic drugs directly to tumor cells.
In one study, researchers used RNA nanoparticles to deliver the chemotherapeutic drug paclitaxel. The second study used RNA nanoparticles that were engineered differently, carrying camptothecin in an animal model and reporting their findings in the journal Advanced Science. RNA nanotechnology has yielded a number of fascinating and important findings.
The study involving paclitaxel found the following:
* 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 by 32,000 times.
* 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 (TNBC) 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 the tumor with little accumulation in vital organs.
Our camptothecin study revealed the following:
* 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 by 1,000 times.
* The RNA nanoparticles displayed cancer-binding ligands as a way to target tumor cells that overexpress the receptors on their surface.
Our studies on RNA nanoparticles demonstrate the feasibility of using RNA nanoparticles to safely and efficiently deliver small-molecule chemotherapeutic drugs to tumor cells. In both studies, these therapeutic RNA nanoparticles were highly stable, had well-defined structure, and showed precise drug loading and targeted delivery.
Another important factor is that, once inside tumor cells, the drug was slowly released from the RNA nanoparticles and retained its ability to kill cancer cells and inhibit tumor growth.
The display of EGFR binding RNA aptamer on the nanoparticles specifically recognized the overexpressed TNBC EGF receptors on the tumor cell surface and increased the uptake of the nanoparticles into tumor cells. Collectively, our data demonstrates the feasibility of RNA nanoparticles for the safe and effective targeted delivery of hydrophobic anti-tumor drugs.
On a personal level, I've been working in this field for decades, and I'm still excited when I see results like these. It's always exciting to see research results that create progress before our eyes. I hope our research in RNA nanotechnology can help to improve care for millions.
PEIXUAN GUO, PHD, is a member of the Translational Therapeutics Program at the OSUCCC - James. He conducts research focusing on the application of RNA nanotechnology for cancer therapy. His lab has developed multifunctional RNA nanoparticles harboring RNA aptamer, siRNA, miRNA, anti-miRNA, ribozymes, and chemical drugs.