Polysalicylic Acid Polymer Microparticle Decoys Therapeutically Treat Acute Respiratory Distress Syndrome

Abstract

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) remain problematic due to high mortality rates and lack of effective treatments. Neutrophilic injury contributes to mortality in ALI/ARDS. Here, technology for rapid ARDS intervention is developed and evaluated, where intravenous salicylic acid-based polymer microparticles, i.e., Poly-Aspirin (Poly-A), interfere with neutrophils in blood, reducing lung neutrophil infiltration and injury in vivo in mouse models of ALI/ARDS. Importantly, Poly-A particles reduce multiple inflammatory cytokines in the airway and bacterial load in the bloodstream in a live bacteria lung infection model of ARDS, drastically improving survival. It is observed that phagocytosis of the Poly-A microparticles, with salicylic acid in the polymer backbone, alters the neutrophil surface expression of adhesion molecules, potentially contributing to their added therapeutic benefits. Given the proven safety profile of the microparticle degradation products-salicylic acid and adipic acid-it is anticipated that the Poly-A particles represent a therapeutic strategy in ARDS with a rare opportunity for rapid clinical translation.

Polymeric particle-based therapies for acute inflammatory diseases

“…PolyAspirin particles more efficiently diverted neutrophils from the inflamed lungs and further reduced inflammatory cytokines compared to non-treated polystyrene and PLGA particles 117 . One suggested mechanism is that interactions between neutrophils and PolyAspirin particles prevent the initial accumulation of neutrophils in the lungs, and the degradation of PolyAspirin may ameliorate inflammation 117 .…”

“…Degradable polymers can be functionalized with a range of anti-inflammatory agents, including aspirin, naproxen and ibuprofen 129 , 130 . The resulting compound can then be synthesized into a particle by single oil–water emulsion 117 , 131 . Intravenous injection of the resulting polymerized salicylic acid (PolyAspirin) particles have shown to alleviate lung inflammation in an endotoxin and a bacterial mouse model of ALI and ARDS, respectively 117 .…”

“…The resulting compound can then be synthesized into a particle by single oil–water emulsion 117 , 131 . Intravenous injection of the resulting polymerized salicylic acid (PolyAspirin) particles have shown to alleviate lung inflammation in an endotoxin and a bacterial mouse model of ALI and ARDS, respectively 117 . PolyAspirin particles more efficiently diverted neutrophils from the inflamed lungs and further reduced inflammatory cytokines compared to non-treated polystyrene and PLGA particles 117 .…”

“…Intravenous injection of the resulting polymerized salicylic acid (PolyAspirin) particles have shown to alleviate lung inflammation in an endotoxin and a bacterial mouse model of ALI and ARDS, respectively 117 . PolyAspirin particles more efficiently diverted neutrophils from the inflamed lungs and further reduced inflammatory cytokines compared to non-treated polystyrene and PLGA particles 117 . One suggested mechanism is that interactions between neutrophils and PolyAspirin particles prevent the initial accumulation of neutrophils in the lungs, and the degradation of PolyAspirin may ameliorate inflammation 117 .…”

“…The primary mechanism by which polymeric particles achieve immunomodulation in the bloodstream is by interaction with WBCs. Phagocytosis of particles by WBCs affects cell physiology, including cytokine release, surface protein expression and gene expression 108 , 114 , 115 , 117 , which leads to the alteration of cell trafficking and signalling (Fig. 2c ).…”