title: Delivery of imatinib-incorporated nanoparticles into lungs suppresses the development of monocrotaline-induced pulmonary arterial hypertension.
abstract: Platelet-derived growth factor (PDGF) is implicated in the pathogenesis of pulmonary arterial hypertension (PAH). Imatinib, a PDGF-receptor tyrosine kinase inhibitor, improved hemodynamics, but serious side effects and drug discontinuation are common when treating PAH. A drug delivery system using nanoparticles (NPs) enables the reduction of side effects while maintaining the effects of the drug. We examined the efficacy of imatinib-incorporated NPs (Ima-NPs) in a rat model and in human PAH-pulmonary arterial smooth muscle cells (PASMCs). Rats received a single intratracheal administration of PBS, FITC-NPs, or Ima-NPs immediately after monocrotaline injection. Three weeks after monocrotaline injection, intratracheal administration of Ima-NPs suppressed the development of pulmonary hypertension, small pulmonary artery remodeling, and right ventricular hypertrophy in the rat model of monocrotaline-induced PAH. We also examined the effects of imatinib and Ima-NPs on PDGF-induced proliferation of human PAH-PASMCs by (3)H-thymidine incorporation. Imatinib and Ima-NPs significantly inhibited proliferation after 24 hours of treatment. Ima-NPs significantly inhibited proliferation compared with imatinib at 24 hours after removal of these drugs. Delivery of Ima-NPs into lungs suppressed the development of MCT-induced PAH by sustained antiproliferative effects on PAS-MCs.
authors.affiliation: Department of Cardiovascular Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Akagi
authors.forename: Kazufumi
authors.initials: K
authors.lastname: Nakamura
authors.forename: Daiji
authors.initials: D
authors.lastname: Miura
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Saito
authors.forename: Hiromi
authors.initials: H
authors.lastname: Matsubara
authors.forename: Aiko
authors.initials: A
authors.lastname: Ogawa
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Matoba
authors.forename: Kensuke
authors.initials: K
authors.lastname: Egashira
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ito
mesh_terms: D000818:Animals; D001549:Benzamides / Q000008:administration & dosage* / Q000627:therapeutic use; D002478:Cells, Cultured; D004195:Disease Models, Animal; D006801:Humans; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000517:prevention & control*; D000068877:Imatinib Mesylate; D008297:Male; D016686:Monocrotaline; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects; D053758:Nanoparticles; D010879:Piperazines / Q000008:administration & dosage* / Q000627:therapeutic use; D011743:Pyrimidines / Q000008:administration & dosage* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors*
chemical_list: D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D016686:Monocrotaline; D000068877:Imatinib Mesylate; C099852:PDGF receptor tyrosine kinase; D017479:Receptors, Platelet-Derived Growth Factor