Delivery of nitric oxide with a pH-responsive nanocarrier for the treatment of renal fibrosis

Fibrosis is an excessive accumulation of extracellular matrix (ECM) that may cause severe organ dysfunction. Nitric oxide (NO), a multifunctional gaseous signaling molecule, may inhibit fibrosis, and delivery of NO may serve as a potential antifibrotic strategy. However, major limitations in the application of NO to treat fibrotic diseases include its nonspecificity, short half-life and low availability in fibrotic tissue. Herein, we aimed to develop a stimuli-responsive drug carrier to deliver NO to halt kidney fibrosis. We manufactured a nanoparticle (NP) composed of pH-sensitive poly[2-(diisopropylamino)ethyl methacrylate (PDPA) polymers to encapsulate a NO donor, a dinitrosyl iron complex (DNIC; [Fe2(μ-SEt)2(NO)4]). The NPs were stable at physiological pH 7.4 but disintegrated at pH 4.0-6.0. The NPs showed significant cytotoxicity to cultured human myofibroblasts and were able to inhibit the activation of myofibroblasts, as indicated by a lower expression level of α-smooth muscle actin and the synthesis of a major ECM component, collagen I, in cultured human myofibroblasts. When given to mice treated with unilateral ureteral ligation/obstruction (UUO) to induce kidney fibrosis, these NPs remained in blood at a stable concentration for as long as 24 h and might enter the fibrotic kidneys to suppress myofibroblast activation and collagen I production, leading to a 70% reduction in the fibrotic area. In summary, our strategy to assemble a NO donor, the iron nitrosyl complex DNIC, into pH-responsive NPs proves effective in treating renal fibrosis and warrants further investigation for its therapeutic potential.