Nitric Oxide Inhaler with Precise Delivery Control for Pulmonary Arterial Hypertension Treatment

Nitric oxide (NO) has been acclaimed as a “miracle molecule”, winning the Nobel Prize in Medicine in 1998 for its role as a signaling messenger. Today, NO is still widely used in various biomedical applications, including wound healing, respiratory, cardiovascular, anticancer, and antibacterial.<br/>Pulmonary arterial hypertension (PAH) is an incurable disease characterized by elevated pressure in the pulmonary arteries due to progressive narrowing and remodeling of blood vessels. This condition leads to increased pulmonary vascular resistance and places a significant strain on the right ventricle of the heart. NO is a powerful regulator of hemodynamics in the cardiovascular system, activating the expression of cyclic guanosine monophosphate (cGMP) in smooth muscle cells (SMCs). Thus, inhaled NO (iNO) act as a potential therapeutic agent for PAH treatment.<br/>However, there are two limitations to the pulmonary delivery of NO via inhalation. First, NO has a concentration-dependent therapeutic effect. Low concentrations of NO (&lt; 400 nm) promote cell proliferation and survival, whereas high concentrations of NO (&gt; 1 µm) induce apoptosis and cell cycle arrest. Therefore, precise control of release behavior is essential to deliver the extremely low concentrations of NO, ranging from picomolar to nanomolar, required for vasodilation. The second limitation is the low bioavailability of NO. The therapeutic effect of NO is impeded due to its short half-life and limited diffusion distance. As a result, the targeted delivery system is required to ensure the action of NO in the PAH lesion.<br/>To achieve this goal, we developed NO inhalers that deliver NO mimicking a healthy endothelial environment into deep lungs by using a nebulizer.<br/>The porous structures were controlled to deliver NO into deep lungs to treat PAH. We prepared two kinds of NO inhalers with different porous structures: the open porous NO inhaler (OPNI) and the closed porous NO inhaler (CPNI). Despite having a large geometric diameter of 20 micrometers, OPNI had a small aerodynamic diameter of about 3.5 micrometers due to its highly porous structure. Furthermore, we confirmed that the stabilization effects by electrostatic interaction between unreacted amines and NONOates retarded NO release. As a result, OPNIs continuously released 0.277 nanomoles of NO, within a range of concentrations produced by endothelial cells, increasing the expression of cGMP in SMCs.<br/>To summarize the presentation, we developed a nebulizer-based NO delivery system that can be an alternative to conventional pulmonary therapies. We anticipate that this translational study will contribute to expanding the potential of NO in various biomedical applications.