title: Liposomal Aerosols of Nitric Oxide (NO) Donor as a Long-Acting Substitute for the Ultra-Short-Acting Inhaled NO in the Treatment of PAH.
abstract: This study seeks to develop a liposomal formulation of diethylenetriamine NONOate (DN), a long acting nitric oxide (NO) donor, with a goal to replace inhaled NO (iNO) in the treatment of pulmonary arterial hypertension (PAH).
  
  
  
  Liposomal formulations were prepared by a lipid film hydration method and modified with a cell penetrating peptide, CAR. The particles were characterized for size, polydispersity index (PDI), zeta potential, entrapment efficiency, storage and nebulization stability, and in-vitro release profiles. The cellular uptake and transport were assessed in rat alveolar macrophages (NR8383) and transforming growth factor β (TGF-β) activated rat pulmonary arterial smooth muscle cells (PASMCs). The fraction of the formulation that enters the systemic circulation, after intratracheal administration, was determined in an Isolated Perfused Rat Lung (IPRL) model. The safety of the formulations were assessed using an MTT assay and by measuring injury markers in the bronchoalveolar lavage (BAL) fluid; the pharmacological efficacy was evaluated by monitoring the changes in the mean pulmonary arterial (mPAP) and systemic pressure (mSAP) in a monocrotaline (MCT) induced-PAH rat model
  
  
  
  Liposome size, zeta potential, and entrapment efficiency were 171 ± 4 nm, -37 ± 3 mV, and 46 ± 5%, respectively. The liposomes released 70 ± 5% of the drug in 8 h and were stable when stored at 4°C. CAR-conjugated-liposomes were taken up more efficiently by PASMCs than liposomes-without-CAR; the uptake of the formulations by rat alveolar macrophages was minimal. DN-liposomes did not increase lung weight, protein quantity, and levels of injury markers in the BAL fluid. Intratracheal CAR-liposomes reduced the entry of liposomes from the lung to blood; the formulations produced a 40% reduction in mPAP for 180 minutes.
  
  
  
  This study establishes the proof-of-concept that peptide modified liposomal formulations of long-acting NO donor can be an alternative to short-acting iNO.
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, 1300 Coulter St, Amarillo, Texas, 79106, USA.
authors.forename: Kamrun
authors.initials: K
authors.lastname: Nahar
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, 1300 Coulter St, Amarillo, Texas, 79106, USA.
authors.forename: Jahidur
authors.initials: J
authors.lastname: Rashid
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, 1300 Coulter St, Amarillo, Texas, 79106, USA.|Office of Generic Drugs, US FDA, 10903 New Hampshire Avenue, Silver Spring, Maryland, 20993, USA.
authors.forename: Shahriar
authors.initials: S
authors.lastname: Absar
authors.affiliation: College of Pharmacy, Prince Sattam Bin Abdulaziz University, P.O. Box 173, Al-Kharj, 11942, Kingdom of Saudi Arabia.
authors.forename: Fahad I
authors.initials: FI
authors.lastname: Al-Saikhan
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, 1300 Coulter St, Amarillo, Texas, 79106, USA. fakhrul.ahsan@ttuhsc.edu.
authors.forename: Fakhrul
authors.initials: F
authors.lastname: Ahsan
mesh_terms: D000280:Administration, Inhalation; D000336:Aerosols / Q000008:administration & dosage*; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002626:Chemistry, Pharmaceutical / Q000379:methods; D004337:Drug Carriers / Q000737:chemistry; D065627:Familial Primary Pulmonary Hypertension / Q000188:drug therapy*; D008081:Liposomes / Q000008:administration & dosage*; D008168:Lung / Q000187:drug effects; D016676:Macrophages, Alveolar / Q000187:drug effects; D009569:Nitric Oxide / Q000008:administration & dosage*; D020030:Nitric Oxide Donors / Q000008:administration & dosage*; D010316:Particle Size; D051381:Rats
chemical_list: D000336:Aerosols; D004337:Drug Carriers; D008081:Liposomes; D020030:Nitric Oxide Donors; D009569:Nitric Oxide
keywords: CAR peptide; inhalation delivery; nitric oxide donor; peptide link liposomes; pulmonary arterial hypertension; targeted drug delivery