Abstract
Clinical outcomes of pulmonary arterial hypertension (PAH) may be improved using targeted delivery system. We investigated the efficacy of ONO1301 (prostacyclin agonist) nanospheres (ONONS) in Sugen5416/hypoxia rat models of PAH. The rats were injected with saline (control) or ONONS (n = 10, each) on days 21 and 28, respectively. Hepatocyte growth factor (HGF)-expressing fibroblasts and inflammatory cytokines were measured. Cardiac performance was assessed and targeted delivery was monitored in vivo, using Texas red-labeled nanoparticles. Compared with control, HGF-expressing fibroblasts and HGF expression levels were significantly higher in the ONONS group, while the levels of interleukin-6, interleukin-1β, transforming growth factor-β, and platelet-derived growth factor were lower. Histological assessment revealed significant amelioration of the percent medial wall thickness in pulmonary vasculature of rats in the ONONS group. Rats in the ONONS group showed decreased proliferating cell nuclear antigen-positive smooth muscle cells and improved right ventricle pressure/left ventricle pressure. No difference was seen in the accumulation of Texas red-labeled nanoparticles in the brain, heart, liver, and spleen between PAH and normal rats. However, a significant area of nanoparticles was detected in the lungs of PAH rats. ONONS effectively ameliorated PAH, with selective delivery to the damaged lung.
Highlights
Clinical outcomes of pulmonary arterial hypertension (PAH) may be improved using targeted delivery system
ONO1301 acted on lung fibroblasts, leading to an elevation of Hepatocyte growth factor (HGF), decrease in inflammatory cytokines, and a suppressive effect on lung vascular smooth muscle proliferation in the lungs of PAH rats
The PAH lung is characterized by inflammatory condition, with elevated TGF-β, platelet derived growth factor-β (PDGF-β), and inflammatory cytokines, including interleukin -6 (IL-6) and IL-1β12–14
Summary
Clinical outcomes of pulmonary arterial hypertension (PAH) may be improved using targeted delivery system. We investigated the efficacy of ONO1301 (prostacyclin agonist) nanospheres (ONONS) in Sugen5416/hypoxia rat models of PAH. ONONS effectively ameliorated PAH, with selective delivery to the damaged lung. ONO1301 is a molecule that exerts long-lasting prostacyclin activity via its inhibitory effect on thromboxane synthase. It is chemically and biologically stable owing to its nonprostanoid s tructure[5,6]. There is a need to develop targeted-drug delivery to the damaged tissue so as to minimize side effects. Containing minimal dose of the drug, to the damaged tissue These nanoparticles have enhanced permeaability across the blood vessels[10,11]
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