Dendrimer micelles with glycyrrhizic acid (GA) were developed for anti-inflammatory therapy of acute lung injury (ALI). Cholesterol was conjugated to histidine-and argininegrafted polyamidoamine (PamHR) for micelle formation. The cholesterol-conjugated PamHR (PamHRchol) was mixed with amphiphilic GA to produce PamHRchol/GA mixed micelles. The GA integrated into the micelles had two functions: it acted as an anti-inflammatory drug and facilitated intracellular gene delivery. The PamHRchol/GA micelles formed stable complexes with plasmid DNA. Integrating GA into the micelles increased their transfection efficiency. Confocal microscopy and flow-cytometry studies confirmed that the PamHRchol/GA micelles improved cellular uptake compared with PamHRchol. A competition assay with free GA suggested that the enhanced transfection efficiency of the micelles might be due to the interaction between GA and its receptor. In addition, GA has a membrane-destabilizing effect, and a chloroquine pretreatment assay confirmed that GA increased endosomal escape. Furthermore, the PamHRchol/GA micelles reduced tumor necrosis factor-α in lipopolysaccharide-activated Raw264.7 cells, suggesting a mechanism for its anti-inflammatory effects. To evaluate the therapeutic potential of the PamHRchol/ GA micelles, the heme oxygenase-1 (HO-1) gene was delivered into the lungs of mice with ALI. The PamHRchol/GA micelles had higher gene delivery efficiency into the lungs than polyethylenimine (25 kDa, PEI25k) and the PamHRchol micelles. The combined effects of the HO-1 gene and GA produced effective anti-inflammation response in the lungs of the ALI animals. Therefore, the dualfunction PamHRchol/GA micelles, which acted as an anti-inflammatory drug and a gene carrier, could be a useful therapy for inflammatory lung diseases.
Pulmonary gene delivery system was developed based on RAGE-antagonist peptide and dexamethasone-conjugated polyamidoamine.
Acute lung injury (ALI) is an inflammatory lung disease. miRNA-92a (miR92a) is induced in the lungs of ALI patients and mediates inflammatory reactions. In this study, a RP1-linked R3V6 (RP1R3V6) peptide was synthesized and evaluated as a carrier of anti-microRNA-92a oligonucleotide (AMO92a) into the lungs of an ALI animal model. In addition to the carrier function, the RP1-linked peptide can have anti-inflammatory effects in the lungs, since RP1 is an antagonist of the receptors for advanced glycation end-products (RAGEs). In a gel retardation assay, the RP1R3V6 peptide formed a spherical complex with AMO92a. In an in vitro delivery assay to L2 rat lung epithelial cells, RP1R3V6 had a lower AMO92a delivery efficiency than R3V6 and polyethyleneimine (PEI25k; 25 kDa). However, RP1R3V6 had an additional anti-inflammatory effect, reducing tumor necrosis factor-α (TNF-α) in lipopolysaccharide-activatedmacrophage cells. With the combined effects of AMO92a and RP1, the RP1R3V6/AMO92a complex reduced the miR92a level more efficiently than did the R3V6/AMO92a and PEI25k/AMO92a complexes. The RP1R3V6/AMO92a complex was administered into the lungs of ALI animals by intratracheal instillation. As a result, the expression of phosphatase and tensin homolog, a target of miR92a, was increased in the lungs. Furthermore, the RP1R3V6/AMO92a complex decreased the TNF-α and interleukin-1β (IL-1β) levels more efficiently than did the PEI25k/AMO92a and R3V6/AMO92a complexes, decreasing the damage in the lungs. These results suggest that RP1R3V6 is a useful carrier of AMO92a and has anti-inflammatory effects in an ALI animal model.
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