Supercharging Macrophages for the Treatment or Prevention of Shock Following Major Trauma.

G. R. Rosania
University of Michigan, Michigan, United States

Keywords: macrophages, formulation, drug delivery, biocrystals, inflammation

Shock is a major cause of mortality following battlefield injury. Physiologically, shock is the visible manifestation of an underlying "cytokine storm" -an uncontrolled inflammatory response caused by the body's own immune system. To treat shock, we have therefore sought to rapidly "supercharge" macrophages with a drug that turns them into potent, anti-inflammatory agents. The scientific premise for this approach is based on the anti-inflammatory activity of clofazimine. Clofazimine is an FDA approved drug used for the treatment of leprosy. It massively bioaccumulates inside macrophages, where it forms, stable insoluble crystal-like drug inclusions (CLDIs). These CLDIs function as mechanopharmaceutical devices by altering the mechanical properties of macrophages. Using mice to study the biological effects of CLDIs, we found that they potently modulate macrophage function and up-regulate production of anti-inflammatory cytokines while down-regulating pro-inflammatory cytokines. For preclinical studies, we have synthesized biomimetic (CLDI-like) formulations of clofazimine hydrochloride and found that they induced a potent anti-inflammatory response when injected into mice, protecting the animals against a lethal endotoxin challenge administered directly into the lungs. Thus, we are seeking to develop an injectable, synthetic, CLDI-like clofazimine formulation to inhibit the cytokine storm, for treating trauma-related shock.