Abstract Body: Background: Interleukin-10 (IL-10) is a potent immunomodulatory cytokine widely explored as a therapy for diseases involving extensive inflammation, for example, inflammatory bowel disease and myocardial infarction (MI). However, IL-10 has a short half-life in vivo, making it necessary to administer large and/or repeated doses that increase the risk of side effects. On the other hand, macrophages (Mφ) play key roles in modulating post-MI cardiac inflammation and recovery. Whether controlled release of IL-10 can program macrophage phenotypes, ameliorate cardiac remodeling, and improve heart function post-MI more efficiently than direct administration of unprotected IL-10 remain to be studied.
Hypothesis and Goals: We hypothesized that coacervate nanoparticles (CoaNP) can be used to create a nano-sized, biomimetic controlled delivery system for IL-10 that protects it from rapid degradation and enhance its bioavailability and potency in programming macrophage phenotypes, which may in turn ameliorate cardiac remodeling after MI.
Methods: CoaNP loaded with recombinant human IL-10 (CoaNP-IL10) was prepared by first mixing IL-10 with natural heparin and then with a synthetic polycation, poly(ethylene argininylaspartate diglyceride) (PEAD). To evaluate the effects of CoaNP-IL10 on programming macrophage phenotypes, we adopted a transwell setup in vitro. To study the efficacy of CoaNP-IL10 on cardiac remodeling in vivo, we used a mouse model of myocardial infarction (MI).
Results: CoaNP-IL10 had an average diameter of 536.23 ± 52.54 nm, prolonging the biostability of IL-10 in vitro. Compared with direct administration of the same doses of unprotected IL-10 (free IL-10), the CoaNP-IL10-500ng group significantly reduced Mφ polarization to an inflammatory phenotype (p<0.01) while promoting Mφ polarization to a noninflammatory phenotype in vitro (p<0.001). Besides, the CoaNP-IL10-100ng group demonstrated the highest enhancement of phagocytosis in noninflammatory macrophages, compared with free 100ng IL-10 (p<0.05). When intramyocardially administered in a mouse MI model, CoaNP-IL10-500ng not only reduced myocardial fibrosis (p<0.05) and CD68+ phagocytic cell infiltration (p<0.001) but also decreased left ventricular dilation (p<0.05) at 6 weeks post-MI, compared with the saline control.
Conclusion: These results suggest that CoaNP-based controlled release of IL-10 efficiently modulates macrophage phenotypes in vitro and cardiac remodeling in vivo.