Feasibility of controlled nitric oxide generation via ascorbate induced chemical reduction of nitrite ions

Inhalable nitric oxide (iNO) is a lifesaving, FDA-approved drug to improve oxygenation in persistent pulmonary hypertension of the newborn. iNO also has many other applications in lung diseases owing to its vasodilatory and antimicrobial effects. However, its wider therapeutic application is often prohibited by the high cost and logistical barriers of traditional NO/N₂ gas tanks. Development of low-cost, portable and tankless nitric oxide (NO) generators is a critical need to advance iNO therapy. Here, we describe the feasibility of NO generation by the controlled reduction of nitrite (NO₂^-) ions. This was accomplished by using ascorbate to reduce NO₂^- ions mediated by a copper(I/II) redox pair complexed by an azo-crown ether ligand ([Cu(II)L]²⁺/[Cu(I)L]⁺) in the solution phase. We found that oxalate, a decomposition product of ascorbate, interferes with the NO generation from the copper-ligand complex. This interference was mitigated, and the reaction was further optimized. NO generation through this method was found to be highly controllable via its proportionality to the flow rate of NO₂^- injected into a reaction chamber containing the reducing components. Hence, this simple approach adds to the current collection of innovative methods under development to obviate the use of NO tanks for iNO delivery.