Innovative therapeutic strategy using prostaglandin I2 agonist (ONO1301) combined with nano drug delivery system for pulmonary arterial hypertension

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.

A novel prostaglandin I2 agonist, ONO-1301, attenuates liver inflammation and suppresses fibrosis in non-alcoholic steatohepatitis model mice

“…Originally, ONO-1301 was developed as an anti-platelet drug; however, a phase I clinical study showed adverse effects such as diarrhea and headache [ 18 ]. Nevertheless, alternative medical effects of ONO-1301 as a cytokine inducer or regeneration inducer were later identified using reduced doses in vitro.…”

“…Thus, ONO-1301 affects the IP receptors expressed in a variety of cells such as fibroblasts, vascular smooth muscle cells, and endothelial cells and upregulates the production of multiple factors, such as VEGF, HGF, and SDF-1, involved in tissue repair [ 14 ]. To date, the therapeutic effects of ONO-1301 have been reported in a variety of diseases, such as pulmonary hypertension, pulmonary fibrosis, arterial vascular disease, cardiac infarction [ 11 , 18 ], and obstructive nephropathy [ 13 ]. Thus, this drug is expected to be used for tissue repair in a variety of diseases and organs.…”

“…ONO-1301SR, which is a poly lactic-co-glycolic acid (PLGA)-polymerized from ONO-1301, was developed to achieve a slow-releasing system of agents into target tissue, and the beneficial effects of ONO-1301SR were confirmed using various animal models of heart failure [ 17 ]. Furthermore, ONO-1301 nanospheres (ONONS) were developed to improve targeted delivery of ONO-1301 and were used to efficiently treat pulmonary artery hypertension [ 18 ]. These modified drugs decreased previously detected adverse effects in human clinical trials.…”

“…ONO-1301 is a unique novel long-lasting prostaglandin (PG) I 2 mimetic with inhibitory activity on thromboxane (TX) A 2 synthase. This drug is chemically and biologically stable because of the lack of a typical prostanoid [ 10 – 18 ]. ONO-1301 acts primarily as a prostacyclin receptor (IP) agonist and can induce adenosine cyclic 3′,5′-monophosphate (cAMP) elevation in target cells.…”

Nanodelivery System for Ovsynch Protocol Improves Ovarian Response, Ovarian Blood Flow Doppler Velocities, and Hormonal Profile of Goats

“…To the best of our knowledge, there are no available studies in the field of estrous synchronization of farm animals that discussed the biological efficiency of nanoengineered PGF 2α . However, some studies referred to the importance of transforming prostaglandin analogs to ensure the accumulation and sustained release of these hormones a long time [ 23 , 24 ].…”