Since his arrival on campus in 2004, molecular biologist and Tech Professor John McDonald has been hard at work developing new solutions and strategies for targeting and treating cancer. Some of his latest research concerns the use of nanoparticles to seek out and deliver treatments to ovarian cancer cells without damaging the body’s healthy cells. Designing this technology has required collaboration between the McDonald Lab in the School of Biology and Andrew Lyon’s lab in the School of Chemistry.
Your lab is designing treatment methods that deliver medications through nanoparticles. What exactly is a nanoparticle?
Basically, they are synthetic particles that are smaller than viruses—there are all kinds of different nanoparticles. The kind we’re developing with the Lyon lab is a nano-hydrogel. They are 98 percent water, and I think of them sort of as microscopic sponges: When you put them in water they swell up and soak up the solution that’s around them. The therapeutic treatment we are using involves small regulatory RNAs [ribonucleic acid], and we use a technique called “breathing in,” because when the particles are exposed to the solution containing the therapeutic RNAs, they self-load the RNA into the particle.
How can a nanoparticle deliver medication to a cancer cell?
The next part of the design is functionalizing the particle. The particle has to be modified in such a way that it binds to the specific cells you want to target. The problem with chemotherapy is that it’s typically given systemically to all exposed cells, not just cancerous cells. In our case, we want to treat only the cancerous cells while leaving the healthy cells alone. This can be accomplished by identifying a surface feature that is unique to the cancer cell, and then engineering the nanoparticle to selectively attach to that feature.
How can a nanoparticle identify a cancer cell in the body?
Nanoparticles injected into the blood stream will circulate through the circulatory system looking for the targeted cancer cells. Once the nanoparticle encounters a cancer cell and attaches to the surface feature, the nanoparticle is taken up by the cell and the therapeutic treatment is slowly released. Nanoparticles have pores in them so that they will release the RNA payload at a controlled rate. In our pilot experiments, we have added a molecule to the nanoparticle that binds to a particular receptor protein that we know is highly expressed on the surface of ovarian cancer cells. In the future, nanoparticles will be designed to target other cell features unique to other types of cancer.
Your therapeutic treatment uses RNA instead of a drug. What is the difference between the two?
Think of the blueprint of the new Engineered Biosystems Building going up on campus. If you’re the guy building the foundation, you’re only interested in examining the section describing how to build the foundation. You don’t care how the roof is built. By analogy, DNA is carried in every cell in our body and is the blueprint of all cellular functions. But liver cells, for example, don’t care how to conduct brain cell functions so they transfer from the DNA blueprint the specific subset of information needed for liver cell function into a type of RNA called mRNA. This mRNA then serves as the template for synthesis of the proteins necessary for liver cell function. Take that concept and apply it to cancer. Cancer is a disease of misinformation. The cell is getting the wrong information—for example, it is being told to rapidly divide when it should remain quiescent. That misinformation could occur due to an error in the DNA blueprinting itself. We call such mistakes “mutations.” Alternatively, there could be a mistake in the flow of information from the DNA such that, for instance, mRNA is being produced when it should not be. The bottom line, in either case, is that abnormal kinds or levels of proteins are produced leading to formation of cancer cells. A new class of cancer drugs are currently being developed to target abnormal or abnormally expressed proteins in cancer cells. Many of these new targeted drugs show great promise but it is estimated that only 10 percent of proteins are “drugable” in this way. Thus, we are interested in developing therapies that can target abnormal or abnormally expressed genes on the mRNA rather than on the protein level. In theory all genes can be targeted on the mRNA level using small inhibitory RNAs. The problem is how do we deliver these inhibitory RNAs specifically to cancer cells? That leads us back to nanoparticles.
What problems are posed by traditional, systemic cancer treatments?
Ideally, we would prefer not to deliver inhibitory (or any) drug treatments systemically because of the unintended inhibitory effects they might have on normal healthy cells. In some cases these “negative side effects” can be quite severe or even lethal.
You’ve been working with Andrew Lyon of the School of Chemistry to develop the nanoparticles. How collaborative has this design process been?
Very collaborative. That’s the beauty of Georgia Tech: You have experts with the specialties you need right next door. I believe this kind of integrated approach will help Georgia Tech significantly contribute to cancer research in the future.
How involved were you with the nanoparticle’s design?
Dr. Lyon’s group had already developed the basic nanoparticle. A former post-doc in my lab, Erin Dickerson, a current research scientist, Roman Mezencev, and I discussed with Dr. Lyon various strategies to further engineer these particles to optimally deliver therapeutic RNAs to ovarian cancer cells. My lab provides the biological knowledge and Dr. Lyon’s lab provides the technical expertise to move the project forward.
What is the next step after designing the nanoparticle?
The next question one asks is, “Does it work?” We first tested the ability of the nanoparticles to deliver the therapeutic RNAs to cancer cells grown in culture. This worked very well which led us to the next level—testing delivery and efficiency in animal models.
Animal testing is currently underway. What obstacles stand in the way of making the treatment available to the public?
There are a number of things the FDA requires before approving any treatment like this for use in humans. We first have to show that these particles are non-toxic in their own right. We have recently demonstrated that this is the case. Now we have to demonstrate efficacy, that is, we have to show that treatment with these particles lowers or reduces the burden of cancer in experimental animals. Once that is validated, one can apply for FDA approval for Phase I experimental trials in humans.
Once the design for ovarian cancer treatment is released, what do you do? Start developing designs for other types of cancer?
At that point, the technology development would be done and the technology would move into the commercial sector. That’s not my area of expertise so I would leave that to someone more qualified. My job as a scientist would be to develop new types of RNAs that might be even more effective in treating different cancers, while using the same or maybe an improved class of delivery vehicles. We continue to work with other Georgia Tech researchers to develop even better delivery systems, as well as new and imaginative cancer diagnostics and therapeutics. It’s all about continued integration and collaboration. That’s one of the great things about being a scientist at Georgia Tech.