Vinod Labhasetwar, PhD, Staff and Endowed Chair in Nanomedicine, Department of Biomedical Engineering, received a 5-year, $2 million grant from the National Institute of Neurological Disorders and Stroke, part of the National Institutes of Health, to investigate a novel stroke therapy that uses a tissue plasminogen activator (tPA) conjugated to nanoparticles. Dr. Labhasetwar is collaborating with M. Shazam Hussain, MD, Director, Cerebrovascular Center at Cleveland Clinic, on this project.
tPA is currently the only medical therapy approved by the Food & Drug Administration (FDA) to dissolve an arterial clot to re-establish blood flow to the brain after a stroke. While tPA is effective, it has a major drawback: it carries a risk of hemorrhage, especially if given more than four and a half hours after a stroke, which can be fatal. Because of this narrow window for treatment, only a small fraction of stroke patients receive tPA treatment, thus profoundly limiting its clinical use.
In addition, tPA can cause a worsening of reperfusion injury, which occurs when blood flow is rapidly restored to tissues devoid of blood and oxygen during a stroke. Reperfusion injury is mediated by excessive production of very damaging molecules (produced by cells under stress) known as reactive oxygen species (ROS). Dr. Labhasetwar sought to counteract the effects of ROS with antioxidant enzymes. Toward that end, he and his team developed a new tPA nanoconjugate in which antioxidant enzymes are encapsulated in nanoparticles attached to tPA.
Nanoparticles are microscopic in nature, and are synthesized in this case using FDA-approved material. Nanoparticles are better able to deliver drugs, particularly those that are susceptible to rapid degradation in the body. In earlier experiments, administration of tPA followed by nanoparticles loaded with antioxidant enzymes was demonstrated to be effective in protecting the brain from reperfusion even when administered six hours after inducing a stroke in an experimental model study.
In this new study, the investigators will test the tPA nanoconjugate, a new dual-action agent that can both dissolve the clot as well as protect the brain, and can potentially be given beyond the time window typically used for tPA alone. Investigators will evaluate how effective this tPA nanoconjugate is in protecting the brain from reperfusion injury and acheiving neurological and functional recovery, all while maintaining the positive thrombolytic effect of tPA.
The ultimate goal is to develop the tPA nanoconjugate as a safe and effective stroke treatment that will reduce the degree of disability for patients and will facilitate recovery. Anticipating additional and larger clinical studies in the future, the team hopes to find the optimal dose of the tPA nanoconjugate to offset the effects of ROS and help stroke patients recover as must neurological and motor function as possible.
Drs. Labhasetwar and Hussain are optimistic about the potential of the new nanoconjugate. “A treatment like this would be effective, safer, and could be given over an extended period of time, which would help more stroke patients,” Dr. Labhasetwar said. “In addition, we could use this tPA nanoconjugate to treat blockages in other organs, such as the heart, and prevent reperfusion injury caused by excess ROS in those organs. This would open up many new treatment possibilities.”