Thomas A. Kent, M.D., Baylor College of Medicine and James M. Tour, Ph.D., Rice University; Traumatic Brain Injury Multidisciplinary Research Consortium Award

Kent: The problem that our project is addressing is the effects of an acute injury to the brain, traumatic brain injury, and we are looking at specifically a kind of injury called oxidative stress.

Tour: It has been known for quite some time that it is reactive oxygen species that are the primary cause of severe degradation to the brain following a traumatic brain injury. It's accompanied with some other injury, usually a loss of blood, for example, and when you couple those two together-the blow to the head followed by a loss of blood, there is a particular damage to the brain that occurs. And even when blood is put back into the individual after the damage occurs, it has been shown in a number of laboratory models that it's that infusion of blood back to save the life of the patient, that lots of the oxygen damage further occurs to the brain.

Kent: Even one episode of low blood pressure after a head injury will dramatically worsen the outcome. There have been many attempts to try to treat this using conventional medications, even using large doses of protective enzymes that the brain has. Unfortunately, all of those attempts have failed, even if they seemed to work in the laboratory. And we think that one reason they may fail is because each of those conventional treatments depend on one of these enzymes that are in the brain to help it along. So we think that because every known treatment for superoxide or oxidative stress depends on something else which may also be consumed in the injury, that that's the reason they fail. So the attraction for us, and the reason that this project is a collaboration between Dr. Tour's laboratory and our laboratory, is that Dr. Tour has evidence that these carbon nanomaterials that he works with are very powerful antioxidants, but they act as sponges. They don't transfer that free radical along and so they don't depend on these other chemicals, which are also being consumed at the same time.

Tour: The carbon nanoparticles are very good at sequestering reactive oxygen species and not only to sequester them but to annihilate them. So most small molecules, if they're radical inhibitors, will receive a reactive free radical and they themselves become a radical. And you try to have those decompose in a way that won't cause other radicals to form. But that's constantly a problem, but the unique thing about the carbon nanoparticles is two radicals when they hit it, they self annihilate each other and there's no more radicals remaining. So you use multiple events to totally annihilate radicals. So rather than transferring the radical, which is the typical mode in the small molecule, these annihilate radicals and in fact these are showing more efficacy than the superoxide dismutase which are the natural protein-based, enzymatic-based methods to deal with radical damage around a cell. These are more effective than even the natural occurring compounds and that's why we're seeing the success.

Kent: Where we stand now is that we've done considerable amount of work to show that in fact these are very strong antioxidants, they work against the most important one of these free radicals, which is superoxide, and that we can now target them to the injury in the brain and specifically on those blood vessels that are injured when you have low blood pressure plus even a mild traumatic brain injury.

Tour: We make the carbon nanoparticles. We make them and show that we can get these in the blood, in solution, and stay that way. We've shown that we can wrap the carbon nanoparticles with antibodies that will cause them to deliver to the right location so this is work that we do here. And then we pass this onto Dr. Kent's group, and then they'll do further work with cells and then go into the animal models. We don't do any of the animal work. That's all done at the hospital.

Kent: What the project does is to bring together chemists with biologists with medical people, and we can all put our heads together and decide how best these new materials may act in the body, what kind of modifications we might make to those materials, and then how best to test them to show that they work. It's kind of unusual to have such a basic and a more clinically oriented group working together like that.

Tour: We need to collaborate because we couldn't do the animal work without them. That's not the type of work that we do. They have surgeons that can do the animal work, that can do the treatment, and the analysis. They need us to prepare the nanoparticles to show how they're made, to show how to keep them in solution, to show how to direct them to certain areas; so both of us are working together with these critical pieces, but we couldn't do it-do much beyond our own specialties.

Kent: So we are very excited about the possibility that we have a treatment that doesn't have the problem of the conventional, pharmacological, and medications that have been used and that also we can target to the injury itself. Our next step is to test these in an animal model of traumatic brain injury. And we are just beginning to do that. We don't have any suggestion that these materials are toxic in any way and so we are looking forward to seeing if they'll have any benefit on improving outcome, reducing the size of the injury, and overall how they might benefit in an animal model.

Tour: Science is wonderful. It is always exciting to me and to my students to be on a project that can have such profound implications. What we hope to do through this is not just solve TBI, but there's all the tangential things that come out-not just in treatment but in education, exciting students, so that they can see these successes and experience the thrill and the joy of science. And that's what the DoD money really helps to support.