Inhaled PLGA particles of prostaglandin E₁ ameliorate symptoms and progression of pulmonary hypertension at a reduced dosing frequency

This study sought to investigate the efficacy of a noninvasive and long acting polymeric particle based formulation of prostaglandin E₁ (PGE₁), a potent pulmonary vasodilator, in alleviating the signs of pulmonary hypertension (PH) and reversing the biochemical changes that occur in the diseased lungs. PH rats, developed by a single subcutaneous injection of monocrotaline (MCT), were treated with two types of polymeric particles of PGE₁, porous and nonporous, and intratracheal or intravenous plain PGE₁. For chronic studies, rats received either intratracheal porous poly(lactic-co-glycolic acid) (PLGA) particles, once- or thrice-a-day, or plain PGE₁ thrice-a-day for 10 days administered intratracheally or intravenously. The influence of formulations on disease progression was studied by measuring the mean pulmonary arterial pressure (MPAP), evaluating right ventricular hypertrophy and assessing various molecular and cellular makers including the degree of muscularization, platelet aggregation, matrix metalloproteinase-2 (MMP-2), and proliferating cell nuclear antigen (PCNA). Both plain PGE₁ and large porous particles of PGE₁ reduced MPAP and right ventricular hypertrophy (RVH) in rats that received the treatments for 10 days. Polymeric porous particles of PGE₁ produced the same effects at a reduced dosing frequency compared to plain PGE₁ and caused minimal off-target effects on systemic hemodynamics. Microscopic and immunohistochemical studies revealed that porous particles of PGE₁ also reduced the degree of muscularization, von Willebrand factor (vWF), and PCNA expression in the lungs of PH rats. Overall, our study suggests that PGE₁ loaded inhalable particulate formulations improve PH symptoms and arrest the progression of disease at a reduced dosing frequency compared to plain PGE₁.