title: 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.
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, 1300 S Coulter, Amarillo, Texas 79106, United States.
authors.forename: Vivek
authors.initials: V
authors.lastname: Gupta
authors.forename: Nilesh
authors.initials: N
authors.lastname: Gupta
authors.forename: Imam H
authors.initials: IH
authors.lastname: Shaik
authors.forename: Reza
authors.initials: R
authors.lastname: Mehvar
authors.forename: Eva
authors.initials: E
authors.lastname: Nozik-Grayck
authors.forename: Ivan F
authors.initials: IF
authors.lastname: McMurtry
authors.forename: Masahiko
authors.initials: M
authors.lastname: Oka
authors.forename: Masanobu
authors.initials: M
authors.lastname: Komatsu
authors.forename: Fakhrul
authors.initials: F
authors.lastname: Ahsan
mesh_terms: D000280:Administration, Inhalation; D000527:Alprostadil / Q000008:administration & dosage*; D000818:Animals; D003692:Delayed-Action Preparations; D004195:Disease Models, Animal; D018450:Disease Progression; D004337:Drug Carriers / Q000737:chemistry; D006439:Hemodynamics / Q000187:drug effects; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D017380:Hypertrophy, Right Ventricular / Q000188:drug therapy / Q000473:pathology; D019344:Lactic Acid / Q000737:chemistry; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D011100:Polyglycolic Acid / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D051381:Rats; D017207:Rats, Sprague-Dawley; D014665:Vasodilator Agents / Q000008:administration & dosage; D014841:von Willebrand Factor / Q000378:metabolism
chemical_list: D003692:Delayed-Action Preparations; D004337:Drug Carriers; D014665:Vasodilator Agents; D014841:von Willebrand Factor; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D020778:Matrix Metalloproteinase 2; C522363:Mmp2 protein, rat; D020780:Matrix Metalloproteinase 9; C572337:Mmp9 protein, rat; D000527:Alprostadil