Nanotechnology Approach for Inhalation Treatment of Pulmonary Fibrosis

纳米技术吸入治疗肺纤维化的方法

基本信息

批准号：
8631723
负责人：
Tamara Minko
金额：
$ 47.93万
依托单位：
RUTGERS, THE STATE UNIV OF N.J.
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-01-01 至 2017-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8631723
关键词：
Address Adverse effects Attention Bleomycin Blood Blood Circulation Breathing Cells Chronic Clinical Collagen Complex Conceptions Cytoskeleton Development Dinoprostone Disadvantaged Disease Dose Drug Delivery Systems Effectiveness Extracellular Matrix Degradation Fibrinogen Fibroblasts Goals HIF1A gene Hamman-Rich syndrome Hypoxia Hypoxia Inducible Factor Immune In Vitro Inflammation Inflammatory Response Interstitial Lung Diseases Investigation Lipids Liposomes Lung Lung Inflammation Lung diseases MMP3 gene Matrix Metalloproteinases Methodology Methods Modification Morbidity - disease rate Mus Nanotechnology Nebulizer Organ Patients Penetration Performance Production Prostaglandin-Endoperoxide Synthase Proteins Public Health Pulmonary Edema Pulmonary Fibrosis Research Role Small Interfering RNA Stream Stromelysin 1 Symptoms Testing Therapeutic Therapeutic Agents Toxic effect Treatment Protocols Treatment outcome base chemokine combinatorial design effective therapy in vivo innovation interstitial lipid mediator mortality mouse model nanocarrier nanoparticle nanostructured nanotherapeutic novel public health relevance research study success therapeutic evaluation traditional therapy

项目摘要

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.

项目名称：吸入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、进行性且常常致命的间质性肺疾病常常导致患者发病和死亡。然而，IPF 的治疗是一项重要的临床任务。挑战，因为这种疾病没有可靠的治疗选择。前列腺素 E2 (PGE2) 环氧合酶衍生的脂质介质，因其在开发和应用中的作用而引起了广泛关注。 IPF 的进展并作为限制免疫炎症反应的可能治疗剂，抑制特定的肺成纤维细胞功能、其增殖和基质蛋白的合成，例如胶原。然而，使用 PGE2 治疗 IPF 的主要挑战是其无法有效地递送到患者体内。肺部和其他器官的严重不良副作用。验证PGE2是否可以成功用于在治疗 IPF 时，我们通过吸入的方式向患有 IPF 的小鼠输送脂质体形式的 PGE2，发现局部 PGE2 的递送具有很高的治疗潜力。 PGE2 的作用与正常化有关负责 IPF 的主要蛋白质的表达。然而，并非所有目标蛋白都有效抑制和 IPF 的一些症状（最显着的是间质性肺水肿、炎症和过多的胶原蛋白）生产）并未完全消除。基于这些观察，我们假设成功 PGE2 和 PGE2 局部肺部联合输送可能会增强 IPF 的治疗效果负责炎症、细胞外基质降解和缺氧损伤的蛋白质抑制剂。因此，本研究的主要目标是开发和测试体内专门设计的吸入剂基于纳米载体的药物递送系统 (DDS)，含有靶向基质的 PGE2 和 siRNA 金属蛋白酶 (MMP3)、趋化因子 (CCL12) 和缺氧诱导因子 1 α (HIF1A)。提案主要致力于（1）纳米结构脂质载体（NLC）的合成和表征 PGE2 和 siRNA 的肺部递送； (2) 鉴定参与该过程的最重要的蛋白质 IPF的发展； (3) siRNA序列的选择； (4)纳米粒子的表征与优化雾化，包括雾化器性能的优化、空气中 DDS 浓度的测定、 DDS动态稳定性分析； (5)测定所递送的DDS在体内的体内分布；和（6）评估所提出的治疗方法在 IPF 小鼠模型中的治疗效果（博莱霉素气管内给药）。计划中的研究解决了治疗中的关键问题 IPF - 治疗效果低下且副作用严重。该应用程序执行概念验证用于同时局部肺部递送 PGE2 和 siRNA 的新型纳米治疗策略的实验 - 主要负责炎症、细胞外基质降解和缺氧的蛋白质抑制剂损害。该项目提出了一种创新的方法和方法来实际实现这一目标概念。