Nanoparticle-mediated endothelial cell-selective delivery of pitavastatin induces functional collateral arteries (therapeutic arteriogenesis) in a rabbit model of chronic hind limb ischemia
Nanoparticle-mediated endothelial cell-selective delivery of pitavastatin induces functional collateral arteries (therapeutic arteriogenesis) in a rabbit model of chronic hind limb ischemia
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DOI：
10.1016/j.jvs.2010.03.020
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发表时间：
2010-08-01
影响因子：
4.3
通讯作者：
Egashira, Kensuke
中科院分区：
文献类型：
--
作者：
Oda, Shinichiro;Nagahama, Ryoji;Egashira, Kensuke
目的：我们最近在一种小鼠模型中证明，纳米颗粒介导的血管内皮细胞注射可有效增加治疗性新生血管。为了开发一种临床适用的方法，有必要进行进一步的研究，以评估该新系统是否可以在较大动物的慢性缺血环境中诱导侧支动脉的形成(动脉生成)。将载药纳米粒(0.05、0.15和0.5 mg/kg)单次注射到缺血肌中。结果：皮塔伐他汀纳米粒(0.5 mg/kg)可诱导血管造影术中可见的动脉生成。肌肉注射磷酸盐缓冲盐水、异硫氰酸荧光素(FITC)纳米颗粒、匹伐他汀(0.5 mg/kg)或匹伐他汀(0.5 mg/kg)纳米颗粒的效果被检测。FITC纳米颗粒主要在缺血肌肉内皮细胞中检测到，最长达4周。用匹伐他汀纳米粒治疗，而不是其他治疗，诱导治疗性动脉生成和改善运动诱导的缺血，提示有功能性侧支动脉的发展。用血管内皮细胞生长因子受体(VEGF)酪氨酸激酶抑制剂vatalanib纳米粒预处理，可取消匹伐他汀纳米粒的治疗效果。通过对缺乏血管内皮生长因子受体酪氨酸激酶的小鼠的单独实验，证实了血管内皮生长因子受体信号在治疗性血管生成中的重要作用。结论：本研究评估的纳米技术平台(纳米颗粒介导的内皮细胞选择性递送匹伐他汀)有望成为临床上可行且有前景的治疗性动脉形成的策略。(《血管外科杂志》2010；52：412-20。)
Objectives: We recently demonstrated in a murine model that nanoparticle-mediated delivery of pitavastatin into vascular endothelial cells effectively increased therapeutic neovascularization. For the development of a clinically applicable approach, further investigations are necessary to assess whether this novel system can induce the development of collateral arteries (arteriogenesis) in a chronic ischemia setting in larger animals.Methods: Chronic hind limb ischemia was induced in rabbits. They were administered single injections of nanoparticles loaded with pitavastatin (0.05, 0.15, and 0.5 mg/kg) into ischemic muscle.Results: Treatment with pitavastatin nanoparticles (0.5 mg/kg), but not other nanoparticles, induced angiographically visible arteriogenesis. The effects of intramuscular injections of phosphate-buffered saline, fluorescein isothiocyanate (FITC)-loaded nanoparticles, pitavastatin (0.5 mg/kg), or pitavastatin (0.5 mg/kg) nanoparticles were examined. FITC nanoparticles were detected mainly in endothelial cells of the ischemic muscles for up to 4 weeks. Treatment with pitavastatin nanoparticles, but not other treatments, induced therapeutic arteriogenesis and ameliorated exercise-induced ischemia, suggesting the development of functional collateral arteries. Pretreatment with nanoparticles loaded with vatalanib, a vascular endothelial growth factor receptor (VEGF) tyrosine kinase inhibitor, abrogated the therapeutic effects of pitavastatin nanoparticles. Separate experiments with mice deficient for VEGF receptor tyrosine kinase demonstrated a crucial role of VEGF receptor signals in the therapeutic angiogenic effects.Conclusions: The nanotechnology platform assessed in this study (nanoparticle-mediated endothelial cell-selective delivery of pitavastatin) may be developed as a clinically feasible and promising strategy for therapeutic arteriogenesis in patients. (J Vasc Surg 2010;52:412-20.)