Cocktail of Superoxide Dismutase and Fasudil Encapsulated in Targeted Liposomes Slows PAH Progression at a Reduced Dosing Frequency.
Currently, two or more pulmonary vasodilators are used to treat pulmonary arterial hypertension (PAH), but conventional vasodilators alone cannot reverse disease progression. In this study, we tested the hypothesis that a combination therapy comprising a vasodilator plus a therapeutic agent that slows pulmonary arterial remodeling and right heart hypertrophy is an efficacious alternative to current vasodilator-based PAH therapy. Thus, we encapsulated a cocktail of superoxide dismutase (SOD), a superoxide scavenger, and fasudil, a specific rho-kinase inhibitor, into a liposomal formulation equipped with a homing peptide, CAR. We evaluated the effect of the formulations on pulmonary hemodynamics in monocrotaline-induced PAH rats (MCT-induced PAH) and assessed the formulation's efficacy in slowing the disease progression in Sugen-5416/hypoxia-induced PAH rats (SU/hypoxia-induced PAH). For acute studies, we monitored both mean pulmonary and systemic arterial pressures (mPAP and mSAP) for 2 to 6 h after a single dose of the plain drugs or formulations. In chronic studies, PAH rats received plain drugs every 48 h and the formulations every 72 h for 21 days. In MCT-induced PAH rats, CAR-modified liposomes containing fasudil plus SOD elicited a more pronounced, prolonged, and selective reduction in mPAP than unmodified liposomes and plain drugs did. In SU/hypoxia-induced PAH rats, the formulation produced a >50% reduction in mPAP and slowed right ventricular hypertrophy. When compared with individual plain drugs or combination, CAR-modified-liposomes containing both drugs reduced the extent of collagen deposition, muscularization of arteries, increased SOD levels in the lungs, and decreased the expression of pSTAT-3 and p-MYPT1. Overall, CAR-modified-liposomes of SOD plus fasudil, given every 72 h, was as efficacious as plain drugs, given every 48 h, suggesting that the formulation can reduce the total drug intake, systemic exposures, and dosing frequency.
Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center , 1300 Coulter Drive, Amarillo, Texas 79106, United States.
Nilesh
N
Gupta
Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center , 1300 Coulter Drive, Amarillo, Texas 79106, United States.
Jahidur
J
Rashid
Developmental Lung Biology, Cardiovascular Pulmonary Research Laboratories, Division of Pulmonary Sciences and Critical Care Medicine, Division of Pediatrics-Critical Care, Departments of Medicine and Pediatrics, University of Colorado, Denver , Anschutz Medical Campus, Aurora, Colorado 80045, United States.
Eva
E
Nozik-Grayck
Departments of Pharmacology and Internal Medicine and the Center for Lung Biology, University of South Alabama , Mobile, Alabama 36688, United States.
Ivan F
IF
McMurtry
Developmental Lung Biology, Cardiovascular Pulmonary Research Laboratories, Division of Pulmonary Sciences and Critical Care Medicine, Division of Pediatrics-Critical Care, Departments of Medicine and Pediatrics, University of Colorado, Denver , Anschutz Medical Campus, Aurora, Colorado 80045, United States.
Kurt R
KR
Stenmark
Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center , 1300 Coulter Drive, Amarillo, Texas 79106, United States.
Fakhrul
0000-0002-1831-4708
F
Ahsan
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D062186:Arterial Pressure / Q000187:drug effects; D002626:Chemistry, Pharmaceutical / Q000379:methods; D006439:Hemodynamics / Q000187:drug effects; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000378:metabolism; D017380:Hypertrophy, Right Ventricular / Q000188:drug therapy / Q000378:metabolism; D008081:Liposomes / Q000494:pharmacology*; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008297:Male; D016686:Monocrotaline / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013482:Superoxide Dismutase / Q000494:pharmacology*; D014665:Vasodilator Agents; D054460:rho-Associated Kinases / Q000378:metabolism
D008081:Liposomes; D014665:Vasodilator Agents; D016686:Monocrotaline; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D013482:Superoxide Dismutase; D054460:rho-Associated Kinases; C049347:fasudil
fasudil; inhalation; liposomes; pulmonary arterial hypertension; super oxide dismutase