Inhaled PLGA Particles of Prostaglandin E₁ Ameliorate Symptoms and Progression of Pulmonary Hypertension at a Reduced Dosing Frequency

Abstract

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.

Development, Optimization, and Characterization of PEGylated Nanoemulsion of Prostaglandin E1 for Long Circulation

“…A number of new alternative dosage forms of PGE1, such as lipid microspheres (15), inhaled PLGA particles (16)(17)(18) for pulmonary arterial hypertension, and nanoparticles (19)(20)(21)(22), can prevent PGE1 from inactivation in blood and improve the efficacy of PGE1. Among these new dosage forms, PGE1 lipid microspheres (lipo-PGE1) were established by Mizushima (15).…”

Pulmonary delivered polymeric micelles – Pharmacokinetic evaluation and biodistribution studies

“…In this context, microparticles [14][15][16][17], liposomes [18][19][20], nanoparticles [21,22], PEG-lipid micelles [23] and nanocrystals [24] have been investigated, and some different nanocarriers have been used to achieve pulmonary sustained release [24][25][26][27][28].…”

Novel therapeutic approaches for pulmonary arterial hypertension: Unique molecular targets to site-specific drug delivery

“…Systemic side-effects of anti-PAH therapies include systemic hypotension, deterioration of right ventricular performance, reduction in right coronary blood flow, increase in shunt function, and reduced oxygenation [6,27].…”

“…With the currently approved therapy and delivery systems, it is not possible to target the pulmonary circulation specifically and that too the diseased area of the same. All of the currently FDA approved therapies elicit their effects in complete circulatory system, when administered via systemic route; and the complete pulmonary vasculature (and systemic circulation to some extent), when administered via non-invasive pulmonary route [6,[27][28][29][30][31].…”

“…In the very first study, Gupta et al reported the applicability of PLGA microparticles for delivering prostaglandin E 1 (PGE 1 ), a selective respiratory vasodilator, via inhalation route [29]. In a sequence of studies, the same research group developed several modified microparticle formulations to enhance the loading efficiency of drug, which include use of cyclodextrin complex and use of cationic polymer (PEI) [27,146]. Higher accumulation and prolonged residence time in the pulmonary arteries.…”