RNA nanoparticles for targeted drug delivery
Original story from Ohio State University (OH, USA).
In a mouse study, RNA micelles shrunk metastasized tumors in lungs.
A new study in mice hints at the potential to use tiny particles made with RNA molecules to deliver chemotherapy drugs and other therapies directly to tumors, killing cancer cells without generating an immune response or toxicity-related side effects. Researchers at Ohio State University (OH, USA) constructed tiny molecular clusters called RNA micelles, loaded them with potent chemo drugs and an RNA molecule that blocks cancer survival, and placed a tumor targeting molecule on their outer wall that attaches to receptors on cancer cell surfaces to enhance delivery.
Treatment with these RNA micelles almost completely depleted metastatic colorectal cancer tumors in mouse lungs within 26 days. The tumors in mice mimicked colorectal cancer that metastasizes to the lung in humans, which comes with a poor prognosis, only 16.2% of patients survive 5 years after diagnosis.
“Developing RNA therapeutic technology is key to treating colorectal cancer lung metastasis because there is no cure,” explained senior study author Peixuan Guo, Sylvan G. Frank Endowed Chair professor in the Division of Pharmaceutics and Pharmacology at The Ohio State University. “We’ve developed a nanoparticle that can treat it efficiently without toxicity – the particle spontaneously targets the cancer and no toxicity is detected.”
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The research coincides with a Nature Protocols publication from Guo’s lab, in which he and colleagues provide detailed instructions on how to construct RNA nanoparticles for targeted delivery of therapeutics combined in one package to produce synergistic treatment effects.
The scientists describe Lego-like architectural structures composed mainly of versatile RNA molecules that have rubber-like properties, all factors that foster cooperation with the body and, as a result, enabling spontaneous tumor targeting and rapid excretion by the kidneys.
“The main idea of the micelle studies is that we can literally prove part of the idea we talk about in the Nature Protocols paper,” shared Kai Jin, first author of the colorectal cancer study and a PhD student in Guo’s lab. “The micelle paper is an example of how a different kind of RNA nanoparticle can be achieved.”
In the study, the researchers doubled the cancer-killing power of the RNA micelles by combining multiple copies of the chemo drug gemcitabine with a molecule called a small interfering RNA to silence the gene encoding for survivin, resulting in treatment of the colon cancer lung metastasis and termination of cancer cell growth, respectively.
“It’s a two-pronged approach. The chemotherapy is killing the cells and the small interfering RNA is blocking survival gene expression,” explained co-author Daniel Binzel, a research assistant professor of pharmaceutics and pharmacology at Ohio State. “The two together help kill the cells in multiple different pathways.”
The team also attached a ligand to the micelles to enhance their attraction to receptors on cancer cell surfaces.
The team initially found in cell culture experiments that delivering gemcitabine and survivin siRNA packaged together in micelles induced DNA damage and programmed cell death in a human colorectal cancer cell line.
In the animal experiments, a six-dose micelle therapy over three weeks started five days after mice were injected with metastatic colorectal cancer cells. Compared to the tumor status in groups of control mice receiving micelles containing either chemo or siRNA alone, the mice receiving micelles loaded with the combined therapeutics were nearly cancer-free. Attaching the ligand to the micelles significantly improved the tumor reduction.
Results showed the micelles attacked the cancer in two ways, accumulating in tumor blood vessels and entering the cells with the ligand’s help.
“We showed that one nanoparticle can carry a drug and therapeutic RNA at the same time, and also used an RNA ligand – these three things are put together so the particle recognizes the cancer cells, binds to them and delivers the particles into the cancer cells,” commented Guo.
Publishing the RNA nanoparticle methodology in Nature Protocols, which publishes only protocols proven to work, comes almost four decades after Guo, as a student in the 1980s, published a paper in Science determining that short segments of noncoding RNA not only existed, but had important functions in cells.
“The recent boom of RNA therapeutics companies and the FDA approval of RNA therapeutics have indicated that my prediction that RNA was the third milestone of pharmaceutical drug development has been realized,” he concluded.
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