Every 40 seconds, someone in the United States has a heart attack, according to the U.S. Centers for Disease Control and Prevention, and about 300,000 of those do not have surgery afterward to restore blood flow. These patients rely on drugs to reduce inflammation and inhibit scar tissue development, or fibrosis, but delivering these drugs to the heart has been challenging.
Jianjun Guan, a materials scientist in the McKelvey School of Engineering at Washington University in St. Louis, has an idea that might eliminate, or at least improve, both of those issues. With a four-year $2.1 million grant from the National Institutes of Health (NIH), Guan and his team plan to enclose a set of proteins designed to curb inflammation and a peptide to prevent fibrosis inside cleverly disguised drug-delivering smart nanoparticles. These nanoparticles would be delivered intravenously into the blood, which would take them directly to the heart.
Existing treatments address inflammation and fibrosis separately but have lacked satisfactory results in clinical trials. Anti-inflammatory drugs can inhibit cardiac repair or are not delivered to the right place at the right time to target inflammatory signals in the heart. Likewise, treatment for cardiac fibrosis typically targets only one pathway to fibrosis and does not prevent other pathways.
Guan’s team aims to explore the secretome of M2 macrophages, or proteins and cytokines secreted by the M2 macrophages designed to reduce inflammation and boost tissue repair, in cardiac therapy. Mohamed Zayed, MD, PhD, a professor of surgery, of radiology and of molecular cell biology at Washington University School of Medicine and of biomedical engineering at McKelvey Engineering, is collaborating with Guan on the research.
“After a heart attack, a dominated cell type in the inflammatory phase is a macrophage called M1, while at the antiinflammatory phase is a macrophage named M2,” said Guan, the Earl E. & Myrtle E. Walker Professor of Engineering and a professor of mechanical engineering and materials science. “If we can quickly deliver the secretome made by the M2 macrophage after a heart attack, it can rapidly transition the inflammatory phase to the antiinflammatory phase.”
To stem cardiac fibrosis, researchers have looked to deliver transforming growth factor beta (TGFβ) and antibodies, but with limited success.
Guan’s team has developed a peptide-based inhibitor, abbreviated RPE, that inhibits TGFβ and other pathways that induce fibrosis. Preliminary studies show that RPE significantly reduced the density of myofibroblasts, or cells found in scar tissue, after a heart attack.
Guan’s plan is to load a nanoparticle with two materials — a secretome of M2 and RPE — and coat the nanoparticle with a platelet membrane from blood so that the immune system recognizes it as part of the blood, Guan said. He also will immobilize a peptide that specifically targets the injury area of the heart.
“When we immobilize such a peptide on the nanoparticle, it forms a brush on the nanoparticle surface,” Guan said. “This brush will recognize the injured area of the heart, go directly to it and gradually release the drugs.”
Guan’s team also will investigate the timing of when the nanoparticles are administered to determine if there is a difference in their effectiveness. They will deliver the drugs in a preclinical model one day, three days and seven days after a heart attack to see if they have a therapeutic effect.
“Our final goal is that we make the nanoparticles available in a form that a patient could inject at home after a heart attack,” Guan said. “We are also looking at a form that they could be inhaled into the lungs and go to the heart.”
Originally published on the McKelvey School of Engineering website.
