Controlled Photochemical Release of Nitric Oxide for Biomedical Applications

用于生物医学应用的一氧化氮的受控光化学释放

• 批准号: 10377507
• 负责人: STEVEN P. SCHWENDEMAN
• 金额: $ 46.83万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-15 至 2024-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10377507
• 关键词: Acute Respiratory Distress Syndrome; Adhesives; Affect; Air; Animal Testing; Animals; Antiviral Agents; Apical; Bacteria; Biological Assay; Blood; Blood capillaries; Cell Culture Techniques; Cell surface; Cells; Chronic; Chronic Obstructive Pulmonary Disease; Clinical; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Devices; Disease; Dose; Electron Microscopy; Epithelial Cells; Exposure to; Feedback; Film; Free Radicals; Frequencies; Funding; Gases; Generations; Grant; Home; Hospitals; Human; IL8 gene; Individual; Infection; Inflammatory; Intensive Care; Ischemic Brain Injury; Knockout Mice; Lactate Dehydrogenase; Light; Lighting; Link; Lung; Lung Transplantation; Lung infections; Malaria; Medical; Medicine; Membrane; Methemoglobin; Methods; Microbial Biofilms; Modeling; Monitor; Morphology; Mus; Mutation; Neonatology; Nitric Oxide; Nitric Oxide Donors; Nitrogen Dioxide; Orphan Drugs; Outcome; Output; Particle Size; Patients; Performance; Phase; Pneumonia; Polymers; Population; Prognosis; Property; Pseudomonas aeruginosa; Pseudomonas aeruginosa infection; Pulmonary Hypertension; Pulmonary Tuberculosis; Reaction; Regimen; Research; Residual state; Respiratory Failure; Respiratory Tract Infections; Risk; S phase; S-Nitrosothiols; S-nitro-N-acetylpenicillamine; Signal Transduction; Sinus; Sinusitis; Solid; Sputum; Stream; Stroke; Surface; System; Technology; Testing; Therapeutic Uses; Tobramycin; Toxic effect; Vasodilator Agents; X ray diffraction analysis; airway epithelium; antimicrobial; antimicrobial drug; base; chronic rhinosinusitis; controlled release; cost; crystallinity; cystic fibrosis airway epithelia; cystic fibrosis patients; cytotoxic; high risk; in vitro testing; in-home care; infection risk; inhaled nitric oxide; light intensity; light microscopy; lung histology; natural antimicrobial; novel strategies; particle; portability; pressure; prevent; prototype; scale up; sensor; solid state

ABSTRACT: Therapeutic use of gas phase nitric oxide (NO) has several important applications in medicine. In addition to its well-known vasodilator action, NO is a potent and endogenous antimicrobial agent normally present at moderate levels (200-1000 ppbv) in the airways/sinuses of healthy individuals, which helps preventing chronic upper airway and lung infections. Since its first medical application >20 years ago, inhaled nitric oxide (iNO) has become a mainstay of intensive care for lung failure patients and it is essential in neonatology, lung transplantation, and pulmonary hypertension. It is also used in pneumonia, acute respiratory distress syndrome (ARDS), and potentially to treat of pulmonary tuberculosis and malaria. With the widespread hospital use of iNO there is a great potential for use of iNO also in the home for treating chronic pulmonary infections related to chronic obstructive pulmonary disease (COPD, ca. 11.5 million cases in US) and chronic rhino sinusitis (CRS, ca. 31 million cases in US). Further, while cases of cystic fibrosis (CF) is less common (ca. 30,000 cases), CF patients possess a genetic defect that greatly reduces NO levels liberated by airway epithelial cells, resulting in very high risk of infection. However, iNO therapy is presently exceedingly expensive (>$3,000 per day) owing to costly NO cylinders and the associated instability of NO in such gas tanks. Therefore, current NO delivery technology is both too expensive and non-portable for potential routine use for in-home care. Using funding from an exploratory R21 grant, our research team has developed a completely new and very attractive method for light-activated NO generation directly from solid phase S-nitrosothiols (RSNO) type NO donors. We have demonstrated that light-activated feedback-controlled release of NO can be achieved precisely from RSNO loaded polymer films combined with variable LED lighting. An amperometric NO selective sensor can provide signals for a feedback circuit to control the LED light intensity to achieve a target level of NO in the output air (or O2) stream. We have identified the main parameters affecting the efficiency of NO release from such films and for minimizing the emitted levels of toxic NO2 gas. In this R01 grant our team will further study the possibilities of scaling up the light-activated NO generation system. We will test the purity of the generated NO gas and the composition of the residual solid decomposition products in order to determine light triggered reaction mechanism of the NO release from the solid state RSNO species. We will study the antimicrobial and cytotoxic properties of the generated NO gas on bacteria infected human epithelial cells and in CFTR knockout mice. This new photochemical gas phase NO generation approach will be very attractive and much lower in cost than using current iNO delivery systems employing high pressure gas tanks. Indeed, photochemically generated NO could eventually be safely extended to in-home use for certain clinical situations (e.g., CF, COPD, CRS and ARDS) to prevent and treat chronic lung infections.

摘要：气相一氧化氮(NO)的治疗用途在医学上有几个重要的应用。在……里面 除了众所周知的血管扩张作用外，一氧化氮通常也是一种有效的内源性抗菌剂 健康人的呼吸道/鼻窦中存在中等水平(200-1000 ppbv)，这有助于预防 慢性上呼吸道和肺部感染。自20年前第一次医学应用以来，吸入一氧化氮 (INO)已成为肺衰竭患者重症监护的支柱，在新生儿、肺 移植和肺动脉高压。它还用于肺炎、急性呼吸窘迫综合征 (抗逆转录病毒药物)，并可能用于治疗肺结核和疟疾。随着iNO在医院的广泛使用 INO在家庭中也有很大的潜力用于治疗与以下相关的慢性肺部感染 慢性阻塞性肺疾病(COPD，美国约1150万例)和慢性鼻窦炎(CRS， 美国约3100万例)。此外，虽然囊性纤维化(CF)的病例较少(约30,000例)，但囊性纤维化 患者存在基因缺陷，极大地降低了呼吸道上皮细胞释放的NO水平，导致 感染的风险非常高。然而，iNO疗法目前非常昂贵(每天3,000美元)，因为 到昂贵的NO钢瓶以及与之相关的此类气罐中NO的不稳定性。因此，目前没有发货 技术太昂贵，而且不便于携带，无法用于家庭护理的潜在常规用途。 利用探索性R21拨款的资金，我们的研究团队开发了一种全新的非常 光激活直接从固相S-亚硝硫醇生成NO的诱人方法 捐赠者。我们已经证明，可以精确地实现光激活反馈控制NO的释放 由RSNO负载聚合物薄膜与可变LED照明相结合。一种电流型非选择性传感器 可以为反馈电路提供信号，以控制LED的光强，以达到目标水平的NO 输出空气(或氧气)流。我们确定了影响NO释放效率的主要参数 这样的薄膜和最大限度地减少有毒NO2气体的排放水平。在这笔R01助学金中，我们团队将进一步研究 扩大光激活的NO生成系统的可能性。我们将测试所产生的 无气体和残存固体分解产物的组成，以确定光触发 固体RSNO物种释放NO的反应机理。我们将研究抗菌剂和 产生的NO气体对细菌感染的人上皮细胞和CFTR基因敲除的细胞毒作用 老鼠。这种新的光化学气相NO生成方法将非常有吸引力，并且成本要低得多 而不是使用目前使用高压气罐的iNO输送系统。事实上，光化学产生的 NO最终可以安全地扩展到某些临床情况下的家庭使用(例如，慢性阻塞性肺疾病、慢性阻塞性肺疾病、慢性阻塞性肺疾病和慢性阻塞性肺疾病) ARDS)预防和治疗慢性肺部感染。