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

基本信息

批准号：
10186743
负责人：
STEVEN P. SCHWENDEMAN
金额：
$ 44.93万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
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/10186743
关键词：
Adhesives Adult Respiratory Distress Syndrome Affect Air Animal Testing Animals Antiviral Agents Apical Bacteria Biological Assay Blood Blood capillaries Cell Culture Techniques Cell surface Cells Chronic Chronic Obstructive Airway 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 Histology 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 natural antimicrobial novel strategies particle portability pressure prevent prototype scale up sensor solid state

项目摘要

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）的治疗用途在医学中有多种重要应用。在除了其众所周知的血管舒张作用，NO是一种有效的内源性抗菌剂在健康个体的气道/鼻窦中以中等水平（200-1000 ppbv）出现慢性上呼吸道和肺部感染。自20年前的第一次医疗应用以来，吸入一氧化氮（INO）已成为对肺衰竭患者重症监护的主要护理，并且在新生儿学中至关重要移植和肺动脉高压。它也用于肺炎，急性呼吸窘迫综合征（ARDS），并有可能治疗肺结核和疟疾。随着广泛的医院使用INO 在家中也有巨大的使用INO来治疗与慢性阻塞性肺疾病（美国COPD，美国1,150万例）和慢性犀牛鼻窦炎（CRS，CRS，大约我们的3100万个案件）。此外，虽然囊性纤维化病例（CF）不太常见（约30,000例），但CF 患者拥有一种遗传缺陷，大大降低了气道上皮细胞释放的水平，导致感染的风险很高。但是，INO治疗目前非常昂贵（每天> $ 3,000）昂贵的无气缸和此类汽油箱中的NO相关的不稳定性。因此，当前没有交货技术既过于昂贵又不容易用于家庭护理的潜在常规使用。使用探索性R21赠款的资金，我们的研究团队开发了一个全新的，非常非常光激活的有吸引力的方法直接从固相S-硝基硫醇（RSNO）型NO中直接产生捐助者。我们已经证明，可以精确地实现光激活的反馈控制NO的释放从RSNO加载的聚合物膜和可变LED照明结合使用。安培计量计无选择传感器可以为反馈电路提供信号，以控制LED光强度，以达到目标NO的目标水平输出空气（或O2）流。我们已经确定了影响不释放效率的主要参数这样的膜，并最大程度地减少发出的有毒NO2气体的水平。在这个R01赠款中，我们的团队将进一步学习扩大光激活的没有生成系统的可能性。我们将测试生成的纯度没有气体和残留固体分解产物的组成，以确定触发的光 NO释放固态RSNO物种的反应机制。我们将研究抗菌和在感染人类上皮细胞的细菌和CFTR敲除的细菌上产生的无气的细胞毒性特性老鼠。这个新的光化学气相没有任何生成方法将非常吸引人，成本要低得多而不是使用使用高压气罐的当前INO输送系统。确实，光化学生成对于某些临床情况，最终可以安全地扩展到家庭用途（例如CF，COPD，CRS和 ARDS）预防和治疗慢性肺部感染。