Nanoparticles will help to complete the inflammatory reaction in time
A new nanomedical drug guarantees timely resolution of inflammation
LifeSciencesToday based on Brigham and Women's Hospital (Clearing Up Inflammation with Pro-resolving Nanomedicines) and Columbia University Medical Center (New Nanomedicine Resolves Inflammation, Promotes Tissue Healing)
Inflammation is the body's natural defense mechanism against the invasion of pathogenic microorganisms and tissue damage. In acute inflammation, pathogens and inflammatory mediators are removed from the body. In chronic inflammatory conditions, the stage of resolution (completion) of the inflammatory process is disrupted.
The resolution of inflammation includes neutralization of chemical mediators, restoration of normal vascular permeability, cessation of leukocyte infiltration and, finally, removal of edematous fluid, protein, leukocytes, foreign agents and necrotic residues – VM.
Currently, it is widely believed that a violation of the resolution of inflammation is one of the main factors contributing to the progression of a number of serious diseases, such as atherosclerosis, arthritis, neurodegenerative diseases and, first of all, cancer. Since the level of inflammation in these diseases is very high, therapeutic drugs with targeted action are needed to contain it.
Scientists at Brigham and Women's Hospital (BWH), Columbia University Medical Center (CUMC), Mount Sinai School of Medicine (School of Medicine at Mount Sinai) and the Massachusetts Institute of Technology (Massachusetts Institute of Technology) have developed the smallest nanoparticles, less than 100 nm in diameter, capable of encapsulate and release a peptide drug that stimulates the stage of resolution of the inflammatory process. They have shown that these particles, which release their therapeutic cargo in a controlled manner for a long time, are a powerful nanopreparation with selective targeting of inflammatory zones. The uniqueness of the new nanoparticles is that their targets are the extracellular microenvironment of inflamed tissue. The particles slowly release their powerful inflammation-resolving cargo in such a way that it spreads through the inflamed tissue. There, the drug binds to receptors on the plasma membrane of activated leukocytes and largely suppresses their activity.
The study was published in the online version of the journal Proceedings of the National Academy of Sciences (Kamaly et al., Development and in vivo efficacy of targeted polymeric inflammation-resolving nanoparticles).
"The beauty of this approach lies in the fact that, unlike many other anti-inflammatory strategies, it uses the principle of nature itself to prevent the development of inflammatory damage, which does not suppress the body's defenses and promotes tissue repair," comments Ira Tabas, senior co-author of the study, MD, PhD, professor. CUMC.
Polymers consisting of three chains have been developed as building blocks of self-organizing targeted nanoparticles. One chain makes possible the capture and controlled release of a therapeutic cargo, in this case a peptide that mimics the pro–resolving properties of the annexin A1 protein, - Ac2-26. The second chain makes the nanoparticles invisible to the immune system and liver, creating conditions for their long-term circulation after systemic administration. Thanks to the third, the nanoparticles become self–guided - their target is the collagen-IV protein in the vascular wall. Thus, nanoparticles are able to selectively attract to the damaged vascular network and release therapeutic anti-inflammatory cargo, where necessary, effectively stimulating the resolution of the inflammatory process.
"These targeted polymer nanoparticles are able in very small doses to prevent infiltration by neutrophils – the most common type of leukocytes – of diseased or injured tissues," says co–lead author Nazila Kamaly, PhD, postdoctoral fellow at BWH. "Their action suppresses the secretion by neutrophils of signaling molecules that can lead to a permanent state of hyperinflammation and further complications of the disease."
"Nanoparticles selectively binding to damaged vessels can play an important role in the treatment of common diseases, such as atherosclerosis, where vascular damage is the basis of pathology. This work offers a new targeted nanopreparation for the developing field of inflammation resolution – a field pioneered by Dr. Charles Serhan from BWH," says study co–lead author Gabrielle Fredman, PhD, postdoctoral fellow at Columbia University Medical Center.
Polymer nanoparticles were tested on mice with peritonitis (inflammation of the peritoneum – the thin membrane lining the inner surface of the abdominal cavity) and with ischemic reperfusion injury of the hind limbs (tissue damage that occurs when blood supply is restored after a period of ischemia).
In mice with peritonitis, intravenous administration of Ac2-26-containing nanoparticles significantly more effectively limited the recruitment of neutrophils, and also accelerated the resolution of the inflammatory process than intravenous administration of Ac2-26 peptide not protected by nanoparticles. In mice with reperfusion injury, nanoparticles reduced tissue damage compared to each of the two types of control nanoparticles – containing the peptide Ac2-26, in which amino acids were "mixed" to make it biologically inactive, and Ac2-26-nanoparticles without a targeting component that makes them a target of collagen-IV.
After injection into the blood, targeted polymer nanoparticles (shown in pink), the target of which is collagen-IV, are concentrated in the area of inflammation. "Self–organizing targeted nanoparticles capable of resolving inflammation can be widely used in medicine, including for the treatment of atherosclerosis," says co-lead author of the study, director of the Laboratory of Nanomedicine and Biomaterials of BWH Omid Farokhzad, MD.
Photo: Farokhzad Lab
Currently, scientists are working on nanoparticles for the treatment of atherosclerosis: preliminary experiments show that they are capable of targeting atherosclerotic plaques.
A patent application has already been filed for targeted polymer nanoparticles that resolve inflammation for the treatment of a number of chronic inflammatory diseases, including atherosclerosis, autoimmune diseases, type 2 diabetes mellitus and Alzheimer's disease.
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