Abstract 11891: Pulmonary Delivery of Novel BEPI/NO-Microparticle for Treatment of Pulmonary Arterial Hypertension

Abstract

Introduction: Pulmonary arterial hypertension (PAH) is an incurable disease characterized by elevated blood pressure in the pulmonary artery causing right heart failure and even sudden cardiac death. Nitric oxide (NO) is a strong potent regulator of PAH. However, the therapeutic effects of exogenous NO depend on its concentration and its half-life is very short. Hypothesis: we prepared NO-releasing inhalers with controlled porous structures to modulate the deposition in lung. Methods and Results: NO-releasing inhalers with micro-sized pores showed improved nebulization efficiency. Furthermore, the cGMP expression and macrophage polarization were evaluated. The fluorescence intensity of Nile red was analyzed using photoluminescence spectroscopy to confirm the amounts of NO-MPs on the slide glass. As with confocal images, 0.8k BPEI/NO-MPs could arrive the lower region than 25k BPEI/NO-MPs. NO produced by endothelial nitric oxide synthase (eNOS) induce vasodilation by increasing cGMP in vascular smooth muscle cells. Hence, the delivery of NO mimicking the physical production of the endothelium in range of 0.05-0.4 nmol cm -2 min -1 is required to restore vascular homeostasis. Therefore, BPEI0.8k/NO-MPs release 0.277 nmol cm -2 min -1 of NO that mimics the environment in healthy endothelium, while BPEI25k/NO-MPs showed a higher concentration as 0.548 nmol cm -2 min -1 . BPEI0.8k/NO-MPs increased the synthesis of cGMP in cells, whereas BPEI25k/NO-MPs presented adverse effects due to an initial burst release. When cell populations were quantified, BPEI0.8k/NO-MPs increased the number of M2-like cells while decreasing the number of M1-like cells. Furthermore, using fluorescence activated cell sorting analysis, proteins and gene levels of cells, anti-inflammatory factors increased in BPEI0.8k/NO-MPs treatment groups Conclusions: novel BPEI/NO-releasing inhalers could deliver NO to deep lungs and has the potential for treatment of PAH