With a four-year, $2.07 million grant from the National Institutes of Health, materials scientist Jianjun Guan and his team at Washington University in St. Louis' McKelvey Institute of Technology have developed a peptide that prevents fibrosis and a series of deceptively disguised drugs. Proteins that reduce inflammation inside delivery smart nanoparticles.
According to the Centers for Disease Control and Prevention (CDC), a heart attack occurs every 40 seconds in the United States, and nearly 300,000 of those victims do not require surgery to restore blood flow. Getting drugs into the hearts of these patients, who rely on drugs to lower inflammation and prevent the formation of scar tissue or fibrosis, has been difficult.
The nanoparticles are injected intravenously through the bloodstream and directly to the heart.
Current treatments target fibrosis and inflammation separately, but their efficacy in clinical studies is insufficient. Anti-inflammatory drugs, when administered at the right time or place, may interfere with heart healing or fail to target inflammatory signals in the heart. Likewise, treatments for cardiac fibrosis typically address only one of the pathways that cause fibrosis and do not block the other pathways.
Guan's team plans to investigate the secretions of M2 macrophages, or the proteins and cytokines they produce, to minimize inflammation and promote tissue healing in heart treatments. Mohamed Zayed, MD, PhD, professor of surgery, radiology, and molecular and cell biology in McKelvey Engineering's School of Medicine and Department of Biomedical Engineering, is working with Guan on the study.
In the inflammatory phase after a heart attack, macrophages, called M1, are the dominant cell type, while in the anti-inflammatory phase, macrophages, called M2, are the dominant cell type. If we can rapidly deliver secretions produced by M2 macrophages after a heart attack, we can quickly transition the inflammatory phase to an anti-inflammatory phase.
Jianjun Guan, materials scientist, McKelvey School of Engineering, Washington University in St. Louis
Researchers have attempted to treat cardiac fibrosis using TGFβ and antibodies, but have had minimal success.
Guan's team created a peptide-based inhibitor (RPE) that inhibits TGFβ and other processes that cause fibrosis. Preliminary studies have shown that RPE significantly reduces the density of myofibroblasts, cells present in scar tissue after a heart attack.
Guan's goal is to load nanoparticles with two components – M2 secretion and RPE – and coat them with platelet membranes so that the immune system recognizes them as part of the blood. He will also anchor specific peptides to the injured area of the heart.
Guan added, “When these peptides are immobilized on nanoparticles, a brush is formed on the nanoparticle surface. These brushes recognize and go directly to injured areas of the heart and gradually release the drug.”
Guan's team also plans to examine the timing of injection of the nanoparticles to see whether there are differences in efficacy. They plan to administer the drug in preclinical models 1, 3, and 7 days after a heart attack to determine whether the treatment is effective.
“Our ultimate goal is to make the nanoparticles available to patients after a heart attack in a form that can be injected at home. A form that can be inhaled into the lungs and travel to the heart is also being considered.”Guan concluded.
Source: https://wustl.edu/