Intratracheal Administration of Prostacyclin Analogue-incorporated Nanoparticles Ameliorates the Development of Monocrotaline and Sugen-Hypoxia-induced Pulmonary Arterial Hypertension.
Intratracheal Administration of Prostacyclin Analogue-incorporated Nanoparticles Ameliorates the Development of Monocrotaline and Sugen-Hypoxia-induced Pulmonary Arterial Hypertension.
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DOI：
10.1097/fjc.0000000000000352
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发表时间：
2016-04
影响因子：
3
通讯作者：
Ito H
中科院分区：
文献类型：
--
作者：
Akagi S;Nakamura K;Matsubara H;Kondo M;Miura D;Matoba T;Egashira K;Ito H
纳米颗粒（NPs）已被用作新型的药物传递系统。局部给药的药物结合NPs可能会优化药物的疗效并减少药物的副作用。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，但会引起导管相关感染等严重副作用。我们研究了气管内给药一种前列腺环素类似物beraprost (BPS)，合并NPs在缺氧-缺氧-常氧大鼠和单罗塔碱PAH模型和人PAH肺动脉平滑肌细胞（PASMCs）中的疗效和安全性。单次给药后，BPS NPs显著降低了2种模型大鼠的右心室压力、右心室肥厚和肺动脉肌肉化。BPS NPs显著提高了单杏仁氨酸大鼠模型的存活率。给予BPS NPs后，肝脏、肾脏、脾脏和心脏均未见炎症细胞浸润、出血或纤维化。血液检查未见肝肾功能异常。处理24小时后，BPS和BPS NPs显著抑制人PAH PASMCs的增殖。在去除BPS NPs后24小时，BPS NPs显著继续抑制人PAH PASMCs的增殖。与非PAH PASMCs相比，BPS NPs显著诱导PAH PASMCs细胞凋亡。气管内给药BPS NPs通过持续的抗增殖作用和对PAH pasmc的促凋亡作用改善PAH大鼠模型的肺动脉高压。
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.