Targeted delivery of glucocorticoids in the treatment of acute lung injury

糖皮质激素靶向递送治疗急性肺损伤

• 批准号: 416293152
• 负责人: Professor Dr. Holger M. Reichardt
• 金额: --
• 依托单位: Institut für Zelluläre und Molekulare Immunologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/416293152?language=en
• 关键词: Targeted; delivery; glucocorticoids; treatment; acute

Glucocorticoids (GC) are used to treat a variety of inflammatory diseases including acute lung injury (ALI). Due to a number of complications, efforts are being made to improve this therapeutic regimen. Besides chemical modification, this can be achieved by using novel nanoformulations that allow targeted GC delivery. One example are inorganic-organic hybrid nanoparticles containing betamethasone (BMP-NP), which have a strong anti-inflammatory potential and preferentially act on cells with high endocytic activity. Since we have found that macrophages are important for GC treatment of ALI in mice, we want to investigate the suitability of BMP-NP to replace the free drug and thereby improve efficacy. We will apply BMP-NP in a mouse model of ALI and analyze leukocyte infiltration, production of pro-inflammatory mediators, alveolar-capillary permeability, and structural changes in the lung. Furthermore, we want to determine the cell types being relevant for BMP-NP treatment by using genetically modified mice selectively lacking the GC receptor in macrophages or airway epithelial cells. Based on these results we will test approaches for an active delivery of BMP-NP to these cell types by coupling them to monoclonal antibodies. Since a thorough characterization of BMP-NP is mandatory for further application, mechanistic studies will be conducted as well. We will investigate the endocytic pathway of BMP-NP uptake and their tissue distribution after intraperitoneal injection in mice by imaging flow cytometry, confocal microscopy, magnetic resonance imaging (MRI) and inductively coupled plasma mass spectrometry (ICP-MS). In combination, these experiments will provide a first impression if BMP-NP have the potential for improving ALI therapy in the future.

糖皮质激素（GC）用于治疗包括急性肺损伤（ALI）在内的多种炎性疾病。由于一些并发症，正在努力改善这种治疗方案。除了化学修饰，这可以通过使用允许靶向GC递送的新型纳米制剂来实现。一个例子是含有betastrin的无机-有机混合纳米颗粒（BMP-NP），其具有强抗炎潜力并且优先作用于具有高内吞活性的细胞。由于我们已经发现巨噬细胞对于GC治疗小鼠中的ALI是重要的，因此我们想要研究BMP-NP替代游离药物的适用性，从而提高功效。我们将应用BMP-NP在急性肺损伤的小鼠模型中，并分析白细胞浸润，促炎介质的产生，肺泡毛细血管通透性和肺结构的变化。此外，我们希望通过使用在巨噬细胞或气道上皮细胞中选择性缺乏GC受体的遗传修饰小鼠来确定与BMP-NP治疗相关的细胞类型。基于这些结果，我们将测试通过将BMP-NP与单克隆抗体偶联而将BMP-NP主动递送至这些细胞类型的方法。由于BMP-NP的彻底表征对于进一步应用是强制性的，因此也将进行机制研究。我们将通过流式细胞术成像、共聚焦显微镜、磁共振成像（MRI）和电感耦合等离子体质谱（ICP-MS）研究小鼠腹腔注射后BMP-NP摄入的内吞途径及其组织分布。结合起来，这些实验将提供BMP-NP是否具有改善未来ALI治疗的潜力的第一印象。