Controlled Photochemical Release of Nitric Oxide for Biomedical Applications

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 除了其众所周知的血管扩张作用外，NO通常是一种有效的内源性抗微生物剂， 在健康个体的气道/鼻窦中以中等水平（200-1000 ppbv）存在，这有助于预防 慢性上呼吸道和肺部感染。自20年前第一次医疗应用以来，吸入一氧化氮 (iNO)已经成为肺衰竭患者重症监护的支柱， 移植和肺动脉高压。它也用于肺炎、急性呼吸窘迫综合征 （ARDS），并可能治疗肺结核和疟疾。随着iNO在医院的广泛使用， 在家庭中使用iNO治疗与以下疾病相关的慢性肺部感染具有很大的潜力 慢性阻塞性肺疾病（COPD，ca. 11.5在美国有100万例）和慢性鼻窦炎（CRS， 约美国3100万例）。此外，虽然囊性纤维化（CF）的病例不太常见（约。30，000例），CF 患者具有极大地降低气道上皮细胞释放的NO水平的遗传缺陷，导致 感染的风险很高。然而，iNO疗法目前非常昂贵（每天> 3，000美元）， 涉及昂贵的NO气缸以及在这种气罐中NO的相关不稳定性。因此，目前没有交付 该技术对于家庭护理的潜在常规使用来说既太昂贵又不便携。 利用探索性R21赠款的资金，我们的研究团队开发了一种全新的， 一种直接从固相S-亚硝基硫醇（RSNO）型NO产生光活化NO的有吸引力的方法 捐助者。我们已经证明，光激活的反馈控制释放NO可以实现精确 从RSNO加载聚合物薄膜结合可变LED照明。电流型NO选择性传感器 可以为反馈电路提供信号，以控制LED光强度，从而在LED中实现NO的目标水平。 输出空气（或O2）流。我们已经确定了影响NO释放效率的主要参数， 这样的膜和用于使有毒NO2气体的排放水平最小化。在这次R 01资助中，我们的团队将进一步研究 扩大光激活NO生成系统的可能性。我们将测试生成的 NO气体和残余固体分解产物的组成，以确定光引发 从固态RSNO物种释放NO的反应机理。我们将研究抗菌剂， 产生的NO气体对细菌感染的人上皮细胞和CFTR敲除中的细胞毒性性质 小鼠这种新的光化学气相NO生成方法将是非常有吸引力的，并且成本低得多 比使用目前的采用高压气罐的iNO输送系统更有效。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，CF、COPD、CRS和 急性呼吸窘迫综合征（ARDS），以预防和治疗慢性肺部感染。

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.