Cocktail of Superoxide Dismutase and Fasudil Encapsulated in Targeted Liposomes Slows PAH Progression at a Reduced Dosing Frequency.
Cocktail of Superoxide Dismutase and Fasudil Encapsulated in Targeted Liposomes Slows PAH Progression at a Reduced Dosing Frequency.
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DOI：
10.1021/acs.molpharmaceut.6b01061
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发表时间：
2017-03-06
影响因子：
4.9
通讯作者：
Ahsan F
中科院分区：
文献类型：
--
作者：
Gupta N;Rashid J;Nozik-Grayck E;McMurtry IF;Stenmark KR;Ahsan F
目前，两种或多种肺血管扩张剂用于治疗肺动脉高压（PAH），但单独使用常规血管扩张剂无法逆转疾病进展。在本研究中，我们检验了一种假设，即由血管扩张剂加一种治疗药物组成的联合治疗可减缓肺动脉重塑和右心肥大，是目前基于血管扩张剂的PAH治疗的有效替代方案。因此，我们将超氧化物歧化酶（SOD）（一种超氧化物清除剂）和法舒地尔（一种特异性rho激酶抑制剂）的混合物封装到配备有归巢肽CAR的脂质体制剂中。我们评价了制剂对野百合碱诱导的PAH大鼠（MCT诱导的PAH）肺血流动力学的影响，并评估了制剂在Sugen-5416/缺氧诱导的PAH大鼠（SU/缺氧诱导的PAH）中减缓疾病进展的疗效。对于急性研究，我们在单剂量普通药物或制剂后监测平均肺动脉压和全身动脉压（mPAP和mSAP）2至6小时。在慢性研究中，PAH大鼠每48小时接受一次普通药物，每72小时接受一次制剂，持续21天。在MCT诱导的PAH大鼠中，含有法舒地尔加SOD的CAR修饰脂质体引起的mPAP降低比未修饰脂质体和普通药物更显著、更持久和更有选择性。在SU/缺氧诱导的PAH大鼠中，该制剂使mPAP降低>50%并减缓右心室肥大。与单独的普通药物或组合相比，含有两种药物的CAR修饰的脂质体减少了胶原沉积的程度，动脉的肌化，增加了肺中的SOD水平，并降低了pSTAT-3和p-MYPT 1的表达。总体而言，每72小时给药一次的SOD加法舒地尔的CAR修饰脂质体与每48小时给药一次的普通药物一样有效，表明该制剂可减少总药物摄入量、全身暴露量和给药频率。
Currently, two or more pulmonary vasodilators are used to treat pulmonary arterial hypertension (PAH), but conventional vasodilators alone cannot reverse disease progression. In this study, we tested the hypothesis that a combination therapy comprising a vasodilator plus a therapeutic agent that slows pulmonary arterial remodeling and right heart hypertrophy is an efficacious alternative to current vasodilator-based PAH therapy. Thus, we encapsulated a cocktail of superoxide dismutase (SOD), a superoxide scavenger, and fasudil, a specific rho-kinase inhibitor, into a liposomal formulation equipped with a homing peptide, CAR. We evaluated the effect of the formulations on pulmonary hemodynamics in monocrotaline-induced PAH rats (MCT-induced PAH) and assessed the formulation’s efficacy in slowing the disease progression in Sugen-5416/hypoxia-induced PAH rats (SU/hypoxia-induced PAH). For acute studies, we monitored both mean pulmonary and systemic arterial pressures (mPAP and mSAP) for 2 to 6 h after a single dose of the plain drugs or formulations. In chronic studies, PAH rats received plain drugs every 48 h and the formulations every 72 h for 21 days. In MCT-induced PAH rats, CAR-modified liposomes containing fasudil plus SOD elicited a more pronounced, prolonged, and selective reduction in mPAP than unmodified liposomes and plain drugs did. In SU/hypoxia-induced PAH rats, the formulation produced a >50% reduction in mPAP and slowed right ventricular hypertrophy. When compared with individual plain drugs or combination, CAR-modified-liposomes containing both drugs reduced the extent of collagen deposition, muscularization of arteries, increased SOD levels in the lungs, and decreased the expression of pSTAT-3 and p-MYPT1. Overall, CAR-modified-liposomes of SOD plus fasudil, given every 72 h, was as efficacious as plain drugs, given every 48 h, suggesting that the formulation can reduce the total drug intake, systemic exposures, and dosing frequency.
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发表时间：
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影响因子：
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