Department of Materials Science and Engineering, Pohang University of Science and Technology (POSTECH), San 31, Hyoja-dong, Nam-gu, Pohang, Kyungbuk 790-784, Republic of Korea.
Biomaterials. 2013 Nov;34(33):8478-90. doi: 10.1016/j.biomaterials.2013.07.062. Epub 2013 Aug 6.
Despite wide exploitation of corticosteroid drugs for the treatment of asthma, the poor therapeutic effect on a neutrophilic subtype of asthma prohibits the full recovery of asthma patients. In this work, dexamethasone (Dexa) was loaded in Flt1 peptide-hyaluronic acid (HA) conjugate nanoparticles to overcome the limitation of corticosteroid resistance for the treatment of neutrophilic pulmonary inflammation. Flt1 peptide-HA conjugates are self-assembled to nanoparticles because of hydrophobic Flt1 peptide conjugated to HA by benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP) chemistry. In vitro bioimaging showed efficient internalization of Flt1 peptide-HA conjugate nanoparticles into lung epithelial cells by HA-receptor mediated endocytosis. Also, ex vivo imaging for the biodistribution in ICR mice revealed long-term retention of Flt1 peptide-HA conjugate nanoparticles in deep lung tissues possibly due to mucoadhesive property of HA. On the basis of bioimaging results for pulmonary drug delivery applications, we prepared Dexa-loaded Flt1 peptide-HA conjugate nanoparticles. Transmission electron microscopy (TEM) and dynamic light scattering (DLS) confirmed the formation of nanoparticles, which reduced cytokine levels of lipopolysaccharide (LPS)-stimulated cells more efficiently than free Dexa. Furthermore, according to the bronchoalveolar lavage (BAL) cellularity and histological analysis, Dexa loaded Flt1 peptide-HA conjugate nanoparticles showed remarkable therapeutic effects in both eosinophilic and neutrophilic asthma model mice.
尽管广泛应用皮质类固醇药物治疗哮喘，但对于哮喘的嗜中性亚型，其治疗效果不佳，限制了哮喘患者的完全康复。在这项工作中，地塞米松（Dexa）被装载到 Flt1 肽-透明质酸（HA）缀合物纳米粒子中，以克服皮质类固醇耐药性的限制，用于治疗嗜中性肺部炎症。Flt1 肽-HA 缀合物由于疏水 Flt1 肽通过苯并三唑-1-基氧基-三（二甲基氨基）膦六氟磷酸盐（BOP）化学与 HA 缀合，自组装成纳米粒子。体外生物成像显示 Flt1 肽-HA 缀合物纳米粒子通过 HA 受体介导的内吞作用有效地进入肺上皮细胞。此外，在 ICR 小鼠中的生物分布的离体成像显示 Flt1 肽-HA 缀合物纳米粒子在深层肺组织中的长期保留，这可能是由于 HA 的粘液附着特性。基于用于肺部药物递送应用的生物成像结果，我们制备了负载地塞米松的 Flt1 肽-HA 缀合物纳米粒子。透射电子显微镜（TEM）和动态光散射（DLS）证实了纳米粒子的形成，与游离地塞米松相比，其更有效地降低了脂多糖（LPS）刺激细胞的细胞因子水平。此外，根据支气管肺泡灌洗（BAL）细胞计数和组织学分析，负载地塞米松的 Flt1 肽-HA 缀合物纳米粒子在嗜酸性粒细胞和嗜中性粒细胞哮喘模型小鼠中均显示出显著的治疗效果。
