Department for Pharmacology and Genetics, Medical University Innsbruck, Innsbruck, Austria.
Department of Pharmaceutical Technology, University Innsbruck, Innsbruck, Austria.
J Control Release. 2017 Mar 28;250:1-8. doi: 10.1016/j.jconrel.2017.02.004. Epub 2017 Feb 3.
Common therapeutic strategies for peripheral arterial disease often fail to re-establish sufficient blood flow within legs and feet of patients for avoiding critical limb ischemia, what is characterized by a substantial risk for amputation. The neuropeptide secretoneurin induces angiogenesis in models of limb and myocardial ischemia and might be a promising tool in the treatment of patients without the option of revascularization therapy for severe ischemia. Within this manuscript, the biologically active part of secretoneurin was identified, modified by induction of a cysteine residue to gain higher stability against enzymatic degradation and further packed into S-protected thiolated chitosan nanoparticles, which enable intra-muscular application of secretoneurin. Secretoneurin nanoparticles restored blood flow in a mouse hind limb ischemia model within one week, whereas control particles did not. In vitro testing also revealed the angiogenic, antiapoptotic and proliferative effects of the new secretoneurin derivate, as tested in primary human umbilical vein endothelial cells. With the work from this study we provide a new promising tool for treatment of peripheral arterial disease.
外周动脉疾病的常见治疗策略往往无法在腿部和脚部重新建立足够的血液流动，以避免严重的肢体缺血，其特征是存在大量截肢的风险。神经肽分泌素在肢体和心肌缺血模型中诱导血管生成，可能是一种有前途的治疗方法，适用于严重缺血而无法进行血运重建治疗的患者。在本手稿中，鉴定了分泌素的生物活性部分，通过诱导半胱氨酸残基来修饰，以获得更高的稳定性，防止酶降解，并进一步包装到 S 保护的巯基化壳聚糖纳米颗粒中，这使得分泌素能够进行肌肉内应用。分泌素纳米颗粒在一周内恢复了小鼠后肢缺血模型中的血液流动，而对照颗粒则没有。体外试验还揭示了新的分泌素衍生物的血管生成、抗凋亡和增殖作用，在原代人脐静脉内皮细胞中进行了测试。通过这项研究的工作，我们提供了一种治疗外周动脉疾病的新的有前途的工具。
