Nitric oxide (NO) is a potent and endogenous antimicrobial/antiviral agent normally present at moderate levels (200-1000 ppbv) within the upper airways/sinuses of healthy patients, helping to prevent chronic upper airway infections. Patients suffering from chronic rhinosinusitis (CRS) and other conditions with difficult-to-treat lower respiratory infections?chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF) and others?could potentially benefit from home treatment with inhaled NO therapy (iNO). While iNO at much higher levels (10- 50 ppmv) is used routinely in hospitals for neonatal pulmonary hypertension and adult acute respiratory distress syndrome, the extremely high cost of current iNO systems ($3,000 per day) precludes their use for home treatment of respiratory tract infections associated with CRS, COPD and CF. For such disorders, administration of doses of NO that mimic levels normally found in the upper airways of healthy individuals could be a safe and effective method of preventing or treating upper and lower respiratory infection. Herein, we propose to study a new low-cost delivery strategy to generate pure nitric oxide (NO) for iNO therapy, which could be used in the hospital or at home for certain clinical situations where no standard chronic treatment currently exists (e.g., CF, COPD, and CRS). We hypothesize that by encapsulating the stable NO-donor, S- nitroso-N-acetylpenicillamine (SNAP), into common polymeric tubing for iNO therapy, light-activated release of NO can be achieved to yield controlled therapeutic NO levels in the carrier air gas. To test this hypothesis, in Aim 1 we will characterize the variables of light active NO release from SNAP-loaded tubing into an airstream. We will load SNAP into polymeric tubing and ambient air will be delivered through the tubing while initiating photolytic NO release with a flood lamp. NO will be monitored to assess how formulation variables in the SNAP-loaded tubing influence the levels and lifetime of photolytic NO release.
In Aim 2, we will combine LED light and a new NO sensor with the optimal SNAP-loaded tubing formulations from Aim 1 to monitor and achieve therapeutic NO levels. We will test how varying humidified air flow rates with optimal tubing type, geometry and SNAP loading can provide continuous, stable levels of NO within the target range of 200-2000 ppbv within an air stream for at least 10 h, using sensor signals to control LED intensity.
In Aim 3, we will examine controlled iNO delivery using the system devised in Aim 2 for its ability to kill bacteria in vitro. We will grow biofilms of P. aureginosa and S. aureus and expose them for various times to specific iNO levels in a range of 200-2000 ppbv with humidified air. Biofilm biomass and viable bacteria will be determined to assess iNO effect derived from the SNAP-loaded tubing. Human tracheal epithelial cells grown on a semipermeable membrane at the air/liquid interface will also be treated with the iNO approach to prove that the produced NO levels have no adverse effects on these cells. The effect of various NO levels produced from the SNAP-loaded tubing on biofilms grown on the surface of the human epithelial cells will also be examined.
Chronic obstructive pulmonary disease (COPD) and chronic rhinosinusitis (CRS) together affect an estimated 15% of the US population and both diseases are associated with frequent respiratory tract infections. Cystic fibrosis (CF) affects a much smaller number of patients (30,000), but their risk for severe infection is greater and long-term prognosis is much poorer than patients with COPD or CRS. Each of these disorders has been linked to abnormally low levels of nitric oxide (NO), a potent endogenous antimicrobial/antiviral agent, within the upper airways of those afflicted with these diseases. In this application, we propose to develop a very inexpensive and simple approach to generate low levels (200-2000 ppbv) of inhaled NO (iNO) for use in the hospital and potentially at home by COPD, CRS and CF patients that will provide increased levels of NO to the airways of these patients during an up to 10 h daily treatment period and, thereby, treating/preventing chronic infections in patients that have these diseases.
| Bailey, Brittany A; Desai, Kashappa-Goud H; Ochyl, Lukasz J et al. (2017) Self-encapsulating Poly(lactic-co-glycolic acid) (PLGA) Microspheres for Intranasal Vaccine Delivery. Mol Pharm 14:3228-3237 |
