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: Satoshi Akagi, Kazufumi Nakamura, Daiji Miura, Yukihiro Saito, Hiromi Matsubara, Aiko Ogawa, Tetsuya Matoba, Kensuke Egashira, Hiroshi Ito
• Journal: International heart journal (Int Heart J) Vol. 56 Issue 3 Pg. 354-9 (May 13 2015) ISSN: 1349-3299 [Electronic] Japan
• PMID: 25902888 (Publication Type: Journal Article)

Chemical References

• Benzamides
• Piperazines
• Pyrimidines
• Monocrotaline
• Imatinib Mesylate
• PDGF receptor tyrosine kinase
• Receptors, Platelet-Derived Growth Factor

Topics

• Animals
• Benzamides (administration & dosage, therapeutic use)
• Cells, Cultured
• Disease Models, Animal
• Humans
• Hypertension, Pulmonary (chemically induced, prevention & control)
• Imatinib Mesylate
• Male
• Monocrotaline
• Muscle, Smooth, Vascular (cytology)
• Myocytes, Smooth Muscle (drug effects)
• Nanoparticles
• Piperazines (administration & dosage, therapeutic use)
• Pyrimidines (administration & dosage, therapeutic use)
• Rats
• Rats, Sprague-Dawley
• Receptors, Platelet-Derived Growth Factor (antagonists & inhibitors)