Akagi Satoshi, Nakamura Kazufumi, Miura Daiji, Saito Yukihiro, Matsubara Hiromi, Ogawa Aiko, Matoba Tetsuya, Egashira Kensuke, Ito Hiroshi
Department of Cardiovascular Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences.
Int Heart J. 2015 May 13;56(3):354-9. doi: 10.1536/ihj.14-338. Epub 2015 Apr 23.
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.
血小板衍生生长因子（PDGF）与肺动脉高压（PAH）的发病机制有关。伊马替尼是一种PDGF受体酪氨酸激酶抑制剂，可改善血流动力学，但在治疗PAH时，严重的副作用和药物停用很常见。使用纳米颗粒（NPs）的药物递送系统能够在维持药物效果的同时减少副作用。我们在大鼠模型和人PAH-肺动脉平滑肌细胞（PASMCs）中研究了载有伊马替尼的纳米颗粒（Ima-NPs）的疗效。大鼠在注射野百合碱后立即经气管内单次给予PBS、FITC-NPs或Ima-NPs。注射野百合碱三周后，经气管内给予Ima-NPs可抑制野百合碱诱导的PAH大鼠模型中肺动脉高压的发展、小肺动脉重塑和右心室肥大。我们还通过掺入³H-胸腺嘧啶核苷研究了伊马替尼和Ima-NPs对人PAH-PASMCs中PDGF诱导的增殖的影响。治疗24小时后，伊马替尼和Ima-NPs显著抑制增殖。在去除这些药物24小时后，与伊马替尼相比，Ima-NPs显著抑制增殖。将Ima-NPs递送至肺部可通过对PAS-MCs的持续抗增殖作用抑制MCT诱导的PAH的发展。
