Repurposing rosiglitazone, a PPAR-γ agonist and oral antidiabetic, as an inhaled formulation, for the treatment of PAH

JOURNAL OF CONTROLLED RELEASE

卷:280

Article

Rashid, Jahidur^1,5  Alobaida, Ahmad¹  Al-Hilal, Taslim A.¹  Hammouda, Samia²  McMurtry, Ivan F.³  Nozik-Grayck, Eva⁴  Stenmark, Kurt R.⁴  Ahsan, Fakhrul¹ 

[1] Texas Tech Univ, Hlth Sci Ctr, Sch Pharm, Dept Pharmaceut Sci, Amarillo, TX 79106 USA

[2] Amer Univ Cairo, Sch Sci & Engn, Cairo, Egypt

[3] Univ S Alabama, Dept Pharmacol, Ctr Lung Biol, Mobile, AL 36688 USA

[4] Univ Colorado Denver, Dept Pediat, Anschutz Med Campus, Aurora, CO 80045 USA

[5] Univ Utah, 295 Chipeta Way,Suite 1S100, Salt Lake City, UT 84108 USA

关键词: Pulmonary arterial hypertension;    PPAR-gamma;    Rosiglitazone;    PLGA particles;    Inhalational delivery;   

DOI  :  10.1016/j.jconrel.2018.04.049

来源: Elsevier

【 摘 要 】

Peroxisome-proliferator-activated-receptor-gamma (PPAR-gamma) is implicated, in some capacity, in the pathogenesis of pulmonary arterial hypertension (PAH). Rosiglitazone, an oral antidiabetic and PPAR-gamma agonist, has the potential to dilate pulmonary arteries and to attenuate arterial remodeling in PAH. Here, we sought to test the hypothesis that rosiglitazone can be repurposed as inhaled formulation for the treatment of PAH. We have tested this conjecture by preparing and optimizing poly(lactic-co-glycolic) acid (PLGA) based particles of rosiglitazone, assessing the drug particles for pulmonary absorption, investigating the efficacy of the plain versus particulate drug formulation in improving the respiratory hemodynamics in PAH animals, and finally studying the effect of the drug in regulating the molecular markers associated with PAH pathogenesis. The optimized particles were slightly porous and spherical, and released 87.9% +/- 6.7% of the drug in 24 h. The elimination half-life of the drug formulated in PLGA particles was 2.5-fold greater than that of the plain drug administered via the same route at the same dose. The optimized formulation, given via the pulmonary route, produced pulmonary selective vasodilation in PAH animals, but oral rosiglitazone had no effect in pulmonary hemodynamics. Rosiglitazone ameliorates the pathogenesis of PAH by balancing the molecular regulators involved in the vasoconstriction and vasodilation of human pulmonary arterial smooth muscle cells. All in all, data generated using intact animal and cellular models point to the conclusion that PLGA particles of an antidiabetic drug can be used for the treatment of a different disease, PAH.

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