Fasudil and DETA NONOate, Loaded in a Peptide-Modified Liposomal Carrier, Slow PAH Progression upon Pulmonary Delivery.
Fasudil and DETA NONOate, Loaded in a Peptide-Modified Liposomal Carrier, Slow PAH Progression upon Pulmonary Delivery.
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DOI：
10.1021/acs.molpharmaceut.7b01003
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发表时间：
2018-05-07
影响因子：
4.9
通讯作者：
Ahsan F
中科院分区：
文献类型：
--
作者：
Rashid J;Nahar K;Raut S;Keshavarz A;Ahsan F
我们研究了联合治疗的可行性，包括法舒地尔，Rho激酶抑制剂，和DETA NONOate（二亚乙基三胺NONOate，DN），一种长效一氧化氮供体，都装载在脂质体修饰的归巢肽，CAR（CARSKNKDC），在治疗肺动脉高压（PAH）。我们首先制备并表征了法舒地尔和DN的未修饰和CAR修饰的脂质体。使用单独的药物或法舒地尔和DN的混合物作为对照，我们研究了两种脂质体制剂在降低野百合碱（MCT）和SUGEN缺氧诱导的PAH大鼠的平均肺动脉压（mPAP）方面的疗效。我们还在用试验和对照制剂处理PAH大鼠后进行了形态测定研究（肌化程度、动脉中壁厚度和胶原沉积）。当对大鼠进行急性和慢性处理时，脂质体制剂处理的大鼠的mPAP降低比普通药物处理的大鼠更明显。CAR修饰的脂质体在降低mPAP方面比药物的未修饰的脂质体更具选择性。这两种药物，在CAR修饰的脂质体中配制，比普通药物的组合更能降低肌化程度、中动脉壁厚度和胶原沉积。如体内数据所示，法舒地尔或DN的CAR修饰的脂质体增加了PAH患者肺动脉平滑肌细胞中血管舒张信号分子cGMP的水平。总体而言，法舒地尔和DN，配制在脂质体中，可用作更好地管理PAH的联合治疗。
We investigated the feasibility of a combination therapy comprising fasudil, a Rho-kinase inhibitor, and DETA NONOate (diethylenetriamine NONOate, DN), a long-acting nitric oxide donor, both loaded in liposomes modified with a homing peptide, CAR (CARSKNKDC), in the treatment of pulmonary arterial hypertension (PAH). We first prepared and characterized unmodified and CAR-modified liposomes of fasudil and DN. Using individual drugs alone or a mixture of fasudil and DN as controls, we studied the efficacy of the two liposomal preparations in reducing mean pulmonary arterial pressure (mPAP) in monocrotaline (MCT) and SUGEN-hypoxia-induced PAH rats. We also conducted morphometric studies (degree of muscularization, arterial medial wall thickness, and collagen deposition) after treating the PAH rats with test and control formulations. When the rats were treated acutely and chronically, the reduction in mPAP was more pronounced in the liposomal formulation-treated rats than in plain drug-treated rats. CAR-modified liposomes were more selective in reducing mPAP than unmodified liposomes of the drugs. Both drugs, formulated in CAR-modified liposomes, reduced the degree of muscularization, medial arterial wall thickness, and collagen deposition more than the combination of plain drugs did. As seen with the in vivo data, CAR-modified liposomes of fasudil or DN increased the levels of the vasodilatory signaling molecule, cGMP, in the smooth muscle cells of PAH-afflicted human pulmonary arteries. Overall, fasudil and DN, formulated in liposomes, could be used as a combination therapy for a better management of PAH.
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DOI：
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发表时间：
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影响因子：
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