Research Project
10282411
SUMMARY Sulfur mustard (SM) is a reactive bifunctional alkylating agent that reacts with a variety of small molecules and macromolecules such as DNA. SM was used as a chemical warfare agent during World War I and many times thereafter. SM and nitrogen mustard (NM) cause severe epithelial and deep tissue injury characterized by acute inflammation, induration, swelling, and blistering upon contact. The influx of immune cells first by neutrophils followed by monocytes and macrophages provide defense to the damaged epithelium; however, with time, persistent inflammation results in an immune storm that incurs additional tissue damage resulting in a long recovery process. Treatment of SM injuries is complicated due to the complexity of the mustard-induced injury combined with variables of exposure concentration and time to therapy. Thus, novel therapies to prevent the deleterious effects of SM exposure is a major unmet need. Our goal is to develop countermeasures using topical and systemic interventions. Specifically we will focus on switching off key cellular events upstream in the injury cascade to limit the immune storm and induction of tissue matrix factors. To achieve this goal, we will undertake a comprehensive nanoparticle-based approach to 1) block monocytes and macrophages from entering injured skin and 2) stabilize SM injured skin to block further release of chemo-attractants for immune cells. We have shown that a high dose systemic administration of vitamin D3 suppresses innate immune cell activity and ameliorates damage to the skin and circulating blood cells following SM and NM exposure. Therefore, combinations of novel nanoparticle-based materials with vitamin D3 may yield positive treatment results. The novel particles that we will test are (i) i.v. administration of poly (lactic-co-glycolic acid) immune modifying microparticles (PLGA-IMPs). These particles have anti-inflammatory properties because they block monocytes and neutrophils from leaving the vessels and entering into sites of tissue injury; (ii) topical application of synthetic, functional high-density lipoprotein nanoparticles (HDL NPs) inherently enhance re-epithelialization following wounding and can act as anti-inflammatory agents; and (iii) topical application of a synthetic mimic of melanin using dopamine formed into spherical polydopamine nanoparticles (PDA NPs). These particles reduce NM-induced inflammation and edema. Our strategy is use systemic infusion of PLGA-IMP to block monocyte and macrophages to mitigate skin and systemic manifestations from NM and SM exposure. We will use HDL NP to target skin and immune cells NF-kB activity, and we will use PDA NPs to topically block acute inflammation. We will also investigate the efficacy of these particles in combination with vitamin D3. Ultimately, these investigations will yield unique treatments for SM-induced injury that will have anti-inflammatory, pro-resolving, capacity with minimal side effects. These novel drugs also will have market sustainability factor by having multiple indications; not only for treating SM injury, but in patients with skin burns.
