Nanotechnology Approach for Inhalation Treatment of Pulmonary Fibrosis

项目名称：吸入性治疗肺纤维化的纳米技术方法 特发性肺纤维化(Ipf)是一种慢性、进行性的、往往致命的间质性肺疾病。 通常会导致患者的发病率和死亡率。然而，特发性肺纤维化的治疗是一项重要的临床研究。 这是一个挑战，因为这种疾病没有可靠的治疗选择。前列腺素E2(PGE2)，a 环氧合酶衍生的脂质介体，因其在肿瘤的发生和发展中的作用而备受关注。 IPF的研究进展及其作为限制免疫-炎症反应的可能的治疗剂， 抑制特定的肺成纤维细胞功能、其增殖和合成基质蛋白，如 胶原蛋白。然而，使用PGE2治疗IPF的主要挑战是它对 对肺部和其他器官有严重的不良副作用。验证PGE2是否可成功用于 治疗IPF时，我们将脂质体PGE2吸入给IPF小鼠，发现局部 前列腺素E_2具有很高的治疗潜力。前列腺素E_2的作用与其归一化作用有关。 参与IPF的主要蛋白质的表达。然而，并不是所有的靶蛋白都是有效的。 抑制和一些IPF的体征(最显著的是间质性肺水肿、炎症和过度胶原蛋白 生产)并未完全消除。基于这些观察，我们假设在 联合局部肺给药PGE_2和PGE_2可提高IPF的治疗效果 负责炎症、细胞外基质降解和缺氧性损伤的蛋白质的抑制物。 因此，这项研究的主要目标是开发并在体内测试一种专门为吸入而设计的 靶向PGE2和siRNA的纳米载体给药系统(DDS) 金属蛋白酶(MMP3)、趋化因子(CCL12)和低氧诱导因子1α(HIF1a)。这项建议 主要研究内容如下：(1)纳米脂质载体的合成与表征 PGE2和siRNA的肺递送；(2)鉴定与PGE2和siRNA有关的最重要的蛋白质 IPF的开发；(3)siRNA序列的选择；(4)纳米粒子的表征和优化 气雾化，包括雾化器性能的优化，空气中DDS浓度的测定， DDS的动态稳定性分析；(5)DDS体内分布的测定；(6) 对IPF小鼠模型的治疗效果评价 (气管内注射博莱霉素)。这项计划中的研究针对的是治疗中的关键问题 IPF-治疗有效率低，不良反应严重。应用程序执行概念验证 一种新型纳米治疗策略同时在肺内局部传递PGE2和siRNA的实验研究 主要负责炎症、细胞外基质降解和低氧的蛋白质的抑制物 损坏。该项目为实际实现这一目标提出了一种创新的途径和方法。 概念。

Project Title: Nanotechnology Approach for Inhalation Treatment of Pulmonary Fibrosis Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive and often fatal form of interstitial lung disease often resulting in patient morbidity and mortality. However, treatment of IPF represents a major clinical challenge since this disorder does not have reliable therapeutic options. Prostaglandin E2 (PGE2), a cyclooxygenase-derived lipid mediator, has attracted considerable attention for its role in the development and progression of IPF and as a possible therapeutic agent for limitation of the immune-inflammatory response, inhibition of specific lung fibroblast functions, their proliferation and synthesis of matrix proteins such as collagen. However, the major challenge in the use of PGE2 for treatment of IPF is its inefficient delivery to the lungs and severe adverse side effects on other organs. To verify that PGE2 can be successfully used for treatment of IPF, we delivered liposomal form of PGE2 via inhalation to the mice with IPF and found that local delivery of PGE2 has a high therapeutic potential. The effect of PGE2 was related to the normalization of the expression of major proteins responsible for the IPF. However, not all targeted proteins were effectively suppressed and some signs of IPF (most notably interstitial lung edema, inflammation, and excessive collagen production) were not completely eliminated. Based on these observations, we hypothesize that the success in the treatment outcome of IPF might be enhanced by combinatorial local lung delivery of PGE2 and suppressors of proteins responsible for inflammation, extracellular matrix degradation, and hypoxic damage. Consequently, the major goal of this study is to develop and test in vivo a specially designed for inhalation nanocarrier-based drug delivery system (DDS) containing PGE2 and siRNA targeted to matrix metalloproteinase (MMP3), chemokine (CCL12) and hypoxia inducible factor one alpha (HIF1A). The proposal is focused mainly on the (1) synthesis and characterization of nanostructured lipid carrier (NLC) for a pulmonary delivery of PGE2 and siRNA; (2) identification of most important proteins involved in the development of IPF; (3) selection of siRNA sequences; (4) characterization and optimization of nanoparticles aerosolization, including optimization of nebulizer performance, determination of airborne DDS concentration, analysis of dynamic stability of DDS; (5) determination of body distribution of delivered DDS in vivo; and (6) evaluation of therapeutic efficiency of the proposed therapeutic approach in a mouse model of IPF (intratracheal administration of bleomycin). The planned research addresses critical problems in treatment of IPF - low effectiveness of therapy and severe adverse side effects. The application performs proof-of-concept experiments of a novel nanotherapeutic strategy for simultaneous local lung delivery of PGE2 and siRNA - suppressors of proteins primarily responsible for inflammation, extra cellular matrix degradation, and hypoxic damage. The project proposes an innovative approach and methodology for the practical realization of this concept.