Therapeutic Neovascularization by Nanotechnology-Mediated Cell-Selective Delivery of Pitavastatin Into the Vascular Endothelium
Therapeutic Neovascularization by Nanotechnology-Mediated Cell-Selective Delivery of Pitavastatin Into the Vascular Endothelium
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DOI：
10.1161/atvbaha.108.182584
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发表时间：
2009-06-01
影响因子：
8.7
通讯作者：
Sunagawa, Kenji
中科院分区：
文献类型：
--
作者：
Kubo, Mitsuki;Egashira, Kensuke;Sunagawa, Kenji
目的-最近使用血管生成生长因子进行治疗性新生血管形成的临床研究表明，其治疗效果比动物实验报告的要小。我们假设纳米颗粒 (NP) 介导的他汀类药物细胞选择性递送至血管内皮将更有效、更综合地诱导治疗性新血管形成。 方法和结果 - 在小鼠后肢缺血模型中，肌内注射可生物降解的聚合物 NP 导致细胞选择性地将 NP 递送至缺血肌肉的毛细血管和小动脉内皮，持续时间长达 2 周。 NP 介导的他汀类药物递送显着增强缺血肢体的血液灌注恢复，增加血管生成和动脉生成，并促进蛋白激酶 Akt、内皮一氧化氮合酶 (eNOS) 和血管生成生长因子的表达。这些效应在给予一氧化氮合酶抑制剂的小鼠或 eNOS 缺陷小鼠中被阻断。 结论：NP 介导的细胞选择性他汀类药物递送可能是治疗严重器官缺血患者新血管形成的更有效和综合策略。 （动脉硬化血栓 Vasc Biol.2009；29：796-801。）
Objective-Recent clinical studies of therapeutic neovascularization using angiogenic growth factors demonstrated smaller therapeutic effects than those reported in animal experiments. We hypothesized that nanoparticle (NP)-mediated cell-selective delivery of statins to vascular endothelium would more effectively and integratively induce therapeutic neovascularization.Methods and Results-In a murine hindlimb ischemia model, intramuscular injection of biodegradable polymeric NP resulted in cell-selective delivery of NP into the capillary and arteriolar endothelium of ischemic muscles for up to 2 weeks postinjection. NP-mediated statin delivery significantly enhanced recovery of blood perfusion to the ischemic limb, increased angiogenesis and arteriogenesis, and promoted expression of the protein kinase Akt, endothelial nitric oxide synthase (eNOS), and angiogenic growth factors. These effects were blocked in mice administered a nitric oxide synthase inhibitor, or in eNOS-deficient mice.Conclusions-NP-mediated cell-selective statin delivery may be a more effective and integrative strategy for therapeutic neovascularization in patients with severe organ ischemia. (Arterioscler Thromb Vasc Biol. 2009; 29: 796-801.)