Pulmonary delivery of curcumin-loaded glycyrrhizic acid nanoparticles for anti-inflammatory therapy.

Acute lung injury (ALI) is an inflammatory disease of the lungs. Curcumin (Cur) shows protective effects in ALI animal models. However, Cur is a hydrophobic drug and its administration into the lungs is inefficient due to its low bioavailability. In this study, glycyrrhizic acid (GA) micelles were produced and evaluated as a carrier of Cur for treatment of ALI. Cur-loaded GA (GA-Cur) nanoparticles were produced using an oil-in-water emulsion/solvent evaporation method. The size and surface charge of the GA-Cur nanoparticles were 159 nm and -23 mV, respectively. In lipopolysaccharide-activated RAW264.7 cells, the GA-Cur nanoparticles decreased the pro-inflammatory cytokine levels more efficiently than GA, Cur, or a simple mixture of GA and Cur (GA + Cur). This suggests that the GA-Cur nanoparticles improved the therapeutic efficiency by enhanced delivery of GA and Cur. GA-Cur inhibited the nuclear translocation of nuclear factor-κb and induced endogenous heme oxygenase-1 more efficiently than the other treatments. Furthermore, an in vitro toxicity test showed that GA-Cur had little cytotoxicity. In vivo therapeutic effects of GA-Cur were evaluated in ALI mouse models. GA-Cur was administered into the animals by intratracheal instillation. The results showed that GA-Cur reduced pro-inflammatory cytokines in a dose-dependent manner and did so more efficiently than GA, Cur, or GA + Cur. Furthermore, the hemolysis and infiltration of monocytes into the lungs were more effectively inhibited by GA-Cur than the other treatments. The data indicate that GA is an efficient carrier of Cur and an anti-inflammatory drug. Owing to their delivery efficiency and safety, GA-Cur nanoparticles will be useful for treatment of ALI.

Combined delivery of curcumin and the heme oxygenase-1 gene using cholesterol-conjugated polyamidoamine for anti-inflammatory therapy in acute lung injury.

BACKGROUND: Acute lung injury (ALI) is an inflammatory lung disease with a high mortality rate. In this study, combined delivery of the anti-inflammatory compound curcumin and the heme-oxygenase-1 (HO-1) gene using cholesterol-conjugated polyamidoamine was evaluated in a mouse model as a therapeutic option for ALI. METHODS: Curcumin was loaded into cholesterol-conjugated polyamidoamine (PamChol) micelles, and curcumin-loaded PamChol (PamChol-Cur) was then complexed with plasmid DNA (pDNA) through charge interactions. The pDNA/PamChol-Cur complex was physically characterized by dynamic light scattering, gel retardation, and heparin competition assay. Gene delivery efficiency was measured by luciferase assay. The HO-1 expression plasmid (pHO-1)/PamChol-Cur complex was administrated into the ALI model via intratracheal injection. The anti-inflammatory effect of the pDNA/PamChol-Cur complex was evaluated by ELISA, immunohistochemistry, and hematoxylin and eosin staining. RESULTS: The pDNA/PamChol-Cur complex had a size of approximately 120 nm with a positive surface charge. The in vitro plasmid DNA (pDNA) delivery efficiency of the pDNA/PamChol-Cur complex into L2 lung epithelial cells was higher than that of pDNA/PamChol. In addition, the curcumin in the pDNA/PamChol-Cur complex inhibited the nuclear translocation of NF-κB, suggesting an anti-inflammatory effect of curcumin. In the ALI animal model, the pHO-1/PamChol-Cur complex delivered the pHO-1 gene more efficiently than pHO-1/PamChol. In addition, the pHO-1/PamChol-Cur complex showed greater anti-inflammatory effects by reducing anti-inflammatory cytokine levels more than delivery of pHO-1/PamChol or PamChol-Cur only. CONCLUSION: The pHO-1/PamChol-Cur complex had a higher pHO-1 gene-delivery efficiency and greater anti-inflammatory effects than the pHO-1/PamChol complex or PamChol-Cur. Therefore, the combined delivery of curcumin and pHO-1 using PamChol-Cur may be useful for treatment of ALI.