Akagi Satoshi, Nakamura Kazufumi, Matsubara Hiromi, Kondo Megumi, Miura Daiji, Matoba Tetsuya, Egashira Kensuke, Ito Hiroshi
*Department of Cardiovascular Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan; †Department of Clinical Science, National Hospital Organization Okayama Medical Center, Okayama, Japan; and ‡Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
J Cardiovasc Pharmacol. 2016 Apr;67(4):290-8. doi: 10.1097/FJC.0000000000000352.
Nanoparticles (NPs) have been used as novel drug delivery systems. Drug-incorporated NPs for local delivery might optimize the efficacy and minimize the side effects of drugs. Intravenous prostacyclin improves long-term survival in patients with pulmonary arterial hypertension (PAH), but it causes serious side effects such as catheter-related infections. We investigated the efficacy and safety of intratracheal administration of a prostacyclin analogue, beraprost (BPS), incorporated NPs in Sugen-hypoxia-normoxia and monocrotaline rat models of PAH and in human PAH pulmonary arterial smooth muscle cells (PASMCs). After a single administration, BPS NPs significantly decreased right ventricular pressure, right ventricular hypertrophy, and pulmonary artery muscularization in the 2 rat models. BPS NPs significantly improved the survival rate in the monocrotaline rat model. No infiltration of inflammatory cells, hemorrhage, or fibrosis was found in the liver, kidney, spleen, and heart after the administration of BPS NPs. No liver or kidney dysfunction was found in the blood examinations. BPS and BPS NPs significantly inhibited the proliferation of human PAH PASMCs after 24 hours of treatment. BPS NPs significantly continued to inhibit the proliferation of human PAH PASMCs at 24 hours after the removal of BPS NPs. BPS NPs significantly induced apoptosis in PAH PASMCs compared to that in non-PAH PASMCs. Intratracheal administration of BPS NPs ameliorates pulmonary hypertension in PAH rat models by a sustained antiproliferative effect and a proapoptotic effect on PAH PASMCs.
纳米颗粒（NPs）已被用作新型药物递送系统。用于局部递送的载药纳米颗粒可能会优化药物疗效并将药物副作用降至最低。静脉注射前列环素可提高肺动脉高压（PAH）患者的长期生存率，但会引起严重的副作用，如导管相关感染。我们在Sugen-低氧-常氧和野百合碱大鼠PAH模型以及人PAH肺动脉平滑肌细胞（PASMCs）中研究了气管内给予载有前列环素类似物贝拉前列素（BPS）的纳米颗粒的疗效和安全性。单次给药后，BPS纳米颗粒在两种大鼠模型中均显著降低了右心室压力、右心室肥厚和肺动脉肌化。BPS纳米颗粒显著提高了野百合碱大鼠模型的生存率。给予BPS纳米颗粒后，在肝脏、肾脏、脾脏和心脏中未发现炎性细胞浸润、出血或纤维化。血液检查未发现肝或肾功能障碍。治疗24小时后，BPS和BPS纳米颗粒均显著抑制人PAH PASMCs的增殖。去除BPS纳米颗粒24小时后，BPS纳米颗粒仍显著抑制人PAH PASMCs的增殖。与非PAH PASMCs相比，BPS纳米颗粒显著诱导PAH PASMCs凋亡。气管内给予BPS纳米颗粒通过对PAH PASMCs的持续抗增殖作用和促凋亡作用改善PAH大鼠模型中的肺动脉高压。
