Abstract 531: Single Administration of a Novel Sustained-release Prostacyclin Analogue Attenuates Monocrotaline-induced Pulmonary Hypertension in Rats
Background: Continuous intravenous infusion of prostacyclin has become recognized as a therapeutic breakthrough for pulmonary arterial hypertension. Nevertheless, prostacyclin therapy requires a continuous infusion device. Poly(d,l-lactic-co-glycolic acid) (PLGA) micro-spheres, which are biodegradable and biocompatible, have been used as a controlled delivery system of proteins, drugs, and other factors. Accordingly, we developed a novel sustained-release prostacyclin analogue encapsulated in PLGA microspheres (ONO-1301MS).
Methods and Results: A single subcutaneous administration of ONO-1301MS allowed sustained elevation of its circulating level for 3 weeks due to degradation of the polymeric matrix in the PLGA microspheres. After monocrotaline (MCT) injection, rats were randomized to receive a single subcutaneous administration of ONO-1301MS or vehicle. There was significant development of pulmonary hypertension 3 weeks after MCT injection. Treatment with ONO-1301MS significantly attenuated increases in right ventricular systolic pressure and ratio of right ventricular weight to body weight in MCT rats. In addition, ONO-1301MS significantly inhibited hypertrophy of the pulmonary vessel wall in MCT rats. Kaplan-Meier survival curves demonstrated that a single administration of ONO-1301MS significantly improved survival rate in MCT rats compared with vehicle administration
Conclusions: We developed a novel sustained-release prostacyclin analogue encapsulated in PLGA microspheres (ONO-1301MS) which allowed 3-week elevation of its circulating level. A single subcutaneous administration of ONO-1301MS attenuated MCT-induced pulmonary hypertension and improved survival in rats. This drug delivery system of a prostacyclin analogue may be a new therapeutic strategy for the treatment of pulmonary arterial hypertension.