Dual-Functional Dendrimer Micelles with Glycyrrhizic Acid for Anti-Inflammatory Therapy of Acute Lung Injury,ACS Applied Materials & Interfaces

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Dual-Functional Dendrimer Micelles with Glycyrrhizic Acid for Anti-Inflammatory Therapy of Acute Lung Injury
ACS Applied Materials & Interfaces ( IF 8.3 ) Pub Date : 2021-09-28 , DOI: 10.1021/acsami.1c08107
Myoungjee Choi ₁ , Le Thi Thuy ₂ , Youngki Lee ₁ , Chunxian Piao ₁ , Joon Sig Choi ₂ , Minhyung Lee ₁

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Dendrimer micelles with glycyrrhizic acid (GA) were developed for anti-inflammatory therapy of acute lung injury (ALI). Cholesterol was conjugated to histidine- and arginine-grafted 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 dual-function PamHRchol/GA micelles, which acted as an anti-inflammatory drug and a gene carrier, could be a useful therapy for inflammatory lung diseases.

中文翻译：

甘草酸双功能树枝状聚合物胶束用于急性肺损伤的抗炎治疗

具有甘草酸 (GA) 的树枝状聚合物胶束被开发用于急性肺损伤 (ALI) 的抗炎治疗。胆固醇与组氨酸和精氨酸接枝的聚酰胺胺 (PamHR) 缀合以形成胶束。胆固醇缀合的 PamHR (PamHRchol) 与两亲性 GA 混合以产生 PamHRchol/GA 混合胶束。整合到胶束中的 GA 有两个功能：它充当抗炎药和促进细胞内基因传递。PamHRchol/GA 胶束与质粒 DNA 形成稳定的复合物。将 GA 整合到胶束中提高了它们的转染效率。共聚焦显微镜和流式细胞术研究证实，与 PamHRchol 相比，PamHRchol/GA 胶束改善了细胞摄取。游离 GA 的竞争试验表明，胶束转染效率的提高可能是由于 GA 与其受体之间的相互作用。此外，GA 具有膜不稳定作用，氯喹预处理试验证实 GA 增加了内体逃逸。此外，PamHRchol/GA 胶束降低了脂多糖激活的 Raw264.7 细胞中的肿瘤坏死因子-α，表明了其抗炎作用的机制。为了评估 PamHRchol/GA 胶束的治疗潜力，将血红素加氧酶 1 (HO-1) 基因输送到患有 ALI 的小鼠的肺中。PamHRchol/GA 胶束比聚乙烯亚胺（25 kDa，PEI25k）和 PamHRchol 胶束具有更高的基因递送效率。HO-1 基因和 GA 的联合作用在 ALI 动物的肺部产生了有效的抗炎反应。因此，作为抗炎药和基因载体的双功能 PamHRchol/GA 胶束可能是治疗炎症性肺病的有效方法。

更新日期：2021-10-13

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