629 PLGA-immune modifying particles as a potential therapy for treating injured skin

Abstract

Inflammatory monocytes, especially macrophages, play key roles in cutaneous wound healing. Immune-modifying particles (IMPs) composed of biodegradable poly(lactic-co-glycolic acid) (PLGA-IMP), an FDA-approved biopolymer, are taken up by blood-borne inflammatory monocytes via the scavenger receptor MARCO (macrophage receptor with collagenous structure). Circulating monocytes have a propensity to engulf particulate material, and daily dosing of PLGA-IMP induces monocyte apoptosis and their sequestration within the spleen. We have shown that PLGA-IMP has anti-inflammatory properties and can block a cytokine storm resulting in improvement of immune-induced pathology in diverse tissues. Using a nitrogen mustard (NM)-induced skin injury model in C57/BL6 mice we examined whether PLGA-IMP intervention is protective from severe acute skin inflammation, induration, swelling and vesication. Here we show that NM-induced skin injury induces infiltration of MARCO+ macrophages. Daily intravenous administration of PLGA-IMP post NM insult decreased infiltration of inflammatory monocytes into the wound area, and significantly reduced skin edema (p<0.0001 days 1 to 5, n=19). PLGA-IMP treatment also delayed eschar formation and significantly promoted skin repair (p=0.047, n=3). Ex vivo analysis of the skin demonstrated reduction in numerous chemokines and inflammatory factors. The most notable effects include a 60% reduction of IL-1β, a hallmark biomarker indicative of NM-induced skin damage (p=0.027, n=4), and a 40% increase in CCL2 (p=0.04, n=9), a chemokine that recruits monocytes to inflammation sites. In summary, we describe a novel therapeutic that protects mice from severe injury following toxic exposure to a chemical insult. PLGA-IMP is in advanced clinical trials and may represent a treatment for life-threatening injuries including burns and toxic skin reactions.