Targeted Delivery of Sildenafil for Inhibiting Pulmonary Vascular Remodeling
Targeted Delivery of Sildenafil for Inhibiting Pulmonary Vascular Remodeling
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西地那非靶向给药抑制肺血管重构
DOI：
10.1161/hypertensionaha.118.11932
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发表时间：
2019-03-01
期刊：
影响因子：
8.3
通讯作者：
Hao, Kun
中科院分区：
文献类型：
--
作者：
Li, Bingbing;He, Wei;Hao, Kun
肺动脉高压是一种由小肺动脉进行性重构引起的致死性肺部疾病。西地那非可以预防PA的重塑，但传统的西地那非制剂因其在PA中的不良蓄积而显示出有限的治疗功效。在此，开发了葡萄糖醛酸（GlcA）修饰的脂质体（GlcA-Lips），以通过靶向GLUT-1（葡萄糖转运蛋白-1）改善西地那非向异常过度增殖的PA平滑肌细胞的递送，从而抑制野百合碱诱导的PA高血压模型中PA的重塑。包封西地那非的GlcA-Lips（GlcA-sildenafil-Lips）具有90 nm的尺寸和pH敏感的药物释放模式。免疫组化染色显示GLUT-1在PA平滑肌细胞中过表达。细胞摄取研究显示，PA平滑肌细胞对GlcA-Lips的摄取增加了1倍，药代动力学和生物分布实验表明，GlcA-Lips的血液循环时间更长，给药8小时后靶向PA的能力增加了1倍。两周治疗表明GlcA-Sildenafil-Lips显著抑制PA重构，PA压力降低32%，中膜增厚减少41%，右心室心肌细胞肥大减少44%，存活率提高。免疫组织化学分析显示，在给予GlcA-Sildenafil-Lips后，caspase-3的表达增强，P-ERK 1/2（磷酸化ERK 1/2）和HK-2（己糖激酶-2）的表达减少，eNOS（内皮型一氧化氮合酶）和cGMP（cGMP）的水平增加。结论：GlcA-Lips靶向给药西地那非可有效抑制野百合碱诱导的肺动脉高压模型肺动脉重构。
Pulmonary arterial hypertension is a fatal lung disease caused by the progressive remodeling of small pulmonary arteries (PAs). Sildenafil can prevent the remodeling of PAs, but conventional sildenafil formulations have shown limited treatment efficacy for their poor accumulation in PAs. Here, glucuronic acid (GlcA)-modified liposomes (GlcA-Lips) were developed to improve the delivery of sildenafil to aberrant over-proliferative PA smooth muscle cells via targeting the GLUT-1 (glucose transport-1), and, therefore, inhibiting the remodeling of PAs in a monocrotaline-induced PA hypertension model. GlcA-Lips encapsulating sildenafil (GlcA-sildenafil-Lips) had a size of 90 nm and a pH-sensitive drug release pattern. Immunostaining assay indicated the overexpression of GLUT-1 in PA smooth muscle cells. Cellular uptake studies showed a 1-fold increase of GlcA-Lips uptake by PA smooth muscle cells and pharmacokinetics and biodistribution experiments indicated longer blood circulation time of GlcA-Lips and increased ability to target PAs by 1-fold after 8 hours administration. Two-week treatment indicated GlcA-sildenafil-Lips significantly inhibited the remodeling of PAs, with a 32% reduction in the PA pressure, a 41% decrease in the medial thickening, and a 44% reduction of the right ventricle cardiomyocyte hypertrophy, and improved survival rate. Immunohistochemical analysis showed enhanced expression of caspase-3, after administration of GlcA-sildenafil-Lips, and reduced expression of P-ERK1/2 (phosphorylated ERK1/2) and HK-2 (hexokinase-2), and increased level of eNOS (endothelial nitric oxide synthase) and cyclic GMP (cGMP). In conclusion, targeted delivery of sildenafil to PA smooth muscle cells with GlcA-Lips could effectively inhibit the remodeling of PAs in the monocrotaline-induced PA hypertension.