Single Injection of a Sustained-release Prostacyclin Analog Improves Pulmonary Hypertension in Rats

Rationale Although prostacyclin is recognized as a therapeutic breakthrough for pulmonary hypertension, it needs continuous infusion because of its short action. Therefore, we developed a new drug delivery system for prostacyclin. We prepared ONO-1301MS, a novel sustained-release prostacyclin analog polymerized with poly(d,l-lactic-co-glycolic acid) (PLGA) microspheres. Objectives We examined whether ONO-1301MS attenuates monocrotaline (MCT)-induced pulmonary hypertension in rats, and attempted to elucidate the underlying mechanisms responsible for the beneficial effects of ONO-1301MS. Methods After MCT injection, rats were randomized to receive a single subcutaneous injection of 100 mg/kg ONO-1301MS or vehicle. Measurements and Main Results We prepared ONO-1301MS, which was polymerized with PLGA to release ONO-1301 for 3 weeks. A single administration of ONO-1301MS achieved sustained elevation of its circulating level and plasma cyclic adenosine 3′,5′-monophosphate level for 3 weeks, and attenuated an increase in a metabolite of thromboxane A2 level. Rats had developed pulmonary hypertension 3 weeks after MCT injection; however, treatment with ONO-1301MS significantly attenuated the increases in right ventricular systolic pressure and right ventricular weight to body weight ratio. ONO-1301MS significantly inhibited hypertrophy of pulmonary arteries. Phosphorylation of extracellular signal-regulated protein kinase (ERK) in the lung was significantly increased in the control group, whereas this increase was markedly attenuated by treatment. Conclusions We developed a new drug delivery system for prostacyclin using PLGA and ONO-1301. A single injection of ONO-1301MS resulted in sustained activity for 3 weeks, and attenuated pulmonary hypertension, partly through its antiproliferative effect on vascular smooth muscle cells via inhibition of ERK phosphorylation.