MicroRNAs have long been attractive therapeutic targets, especially for cancer. However, the therapeutic potential of microRNA replacement has been limited by delivery issues. That might be changing. Yesterday, in Science Translation Medicine, researchers at Purdue University reported on a method for delivering tumor-suppressing microRNAs that eliminates the need for toxic delivery vehicles.
"RNAs are inherently unstable; they're subject to being degraded in the bloodstream. It's been hypothesized that if we want to use RNA as a therapy, we have to protect it," said Andrea Kasinski, a biology professor at Purdue and co-author on the study. "Protective vehicles are usually some sort of nanoparticle, often a lipid-encapsulated particle. Although the RNA is protected, the protection typically comes at a price.” These particles tend to be a little larger, so penetrating the dense architecture of the tumor can be difficult, she added.
In their study, Kasinski's team conjugated the RNA to a molecule of folate. "Folate is generally pro-growth. That's why cancer cells overexpress the receptor—they want more folate," Kasinski said. "We're just hijacking that idea and saying, 'Okay, you can have all the folate you want, but we're going to conjugate it to a warhead that will hopefully knock out the cancer cell.'"
Unprotected RNAs can be degraded by two mechanisms—an exonuclease, which cuts the ends and chews inward, or an endonuclease, which cuts into the middle. By attaching the RNA to a folate, the researchers protected at least one end. Whether this is the end that usually gets chewed into, they're not sure, but folate appears to stabilize the RNA.
So far this method has only been tested in mice and the same microRNA used in this study, miR-34a, failed in clinical trials. However, Kasinski's team believes that one of the reasons it failed is because of the delivery vehicle. Even if the RNA is somehow toxic, they're delivering it at a much lower dose than what was used in the trial, and whatever isn't taken up by the tumor is cleared from the organism very fast.
While this kind of therapy may not replace other methods for cancer treatment, it could help make others more effective. Given in combination with chemotherapy, for instance, it would break down the cells' defenses, making them more sensitive to the cytotoxic agent.