Heun Yvonn, Hildebrand Staffan, Heidsieck Alexandra, Gleich Bernhard, Anton Martina, Pircher Joachim, Ribeiro Andrea, Mykhaylyk Olga, Eberbeck Dietmar, Wenzel Daniela, Pfeifer Alexander, Woernle Markus, Krötz Florian, Pohl Ulrich, Mannell Hanna
Walter Brendel Centre of Experimental Medicine, BMC, Ludwig-Maximilians-University, Großhaderner Str. 9, 82152 Planegg, Germany.; DZHK (German Center for Cardiovascular Research) partner site Munich Heart Alliance, Munich.
Institute of Pharmacology and Toxicology, Biomedical Center University of Bonn, Sigmund-Freud-Strasse 25, 53105 Bonn, Germany.
Theranostics. 2017 Jan 1;7(2):295-307. doi: 10.7150/thno.16192. eCollection 2017.
In the field of vascular gene therapy, targeting systems are promising advancements to improve site-specificity of gene delivery. Here, we studied whether incorporation of magnetic nanoparticles (MNP) with different magnetic properties into ultrasound sensitive microbubbles may represent an efficient way to enable gene targeting in the vascular system after systemic application. Thus, we associated novel silicon oxide-coated magnetic nanoparticle containing microbubbles (SO-Mag MMB) with lentiviral particles carrying therapeutic genes and determined their physico-chemical as well as biological properties compared to MMB coated with polyethylenimine-coated magnetic nanoparticles (PEI-Mag MMB). While there were no differences between both MMB types concerning size and lentivirus binding, SO-Mag MMB exhibited superior characteristics regarding magnetic moment, magnetizability as well as transduction efficiency under static and flow conditions . Focal disruption of lentiviral SO-Mag MMB by ultrasound within isolated vessels exposed to an external magnetic field decisively improved localized VEGF expression in aortic endothelium and enhanced the angiogenic response. Using the same system , we achieved a highly effective, site-specific lentiviral transgene expression in microvessels of the mouse dorsal skin after arterial injection. Thus, we established a novel lentiviral MMB technique, which has great potential towards site-directed vascular gene therapy.
在血管基因治疗领域，靶向系统是有望提高基因递送位点特异性的进展。在此，我们研究了将具有不同磁性的磁性纳米颗粒（MNP）掺入超声敏感微泡中是否可能是一种在全身应用后实现血管系统中基因靶向的有效方法。因此，我们将含有新型氧化硅涂层磁性纳米颗粒的微泡（SO-Mag MMB）与携带治疗性基因的慢病毒颗粒相结合，并与涂有聚乙烯亚胺涂层磁性纳米颗粒的微泡（PEI-Mag MMB）相比，确定了它们的物理化学性质和生物学性质。虽然两种微泡类型在大小和慢病毒结合方面没有差异，但SO-Mag MMB在静态和流动条件下的磁矩、磁化率以及转导效率方面表现出优异的特性。在暴露于外部磁场的离体血管内，通过超声对携带慢病毒的SO-Mag MMB进行聚焦破坏，决定性地改善了主动脉内皮中局部VEGF的表达，并增强了血管生成反应。使用相同的系统，我们在动脉注射后在小鼠背部皮肤的微血管中实现了高效、位点特异性的慢病毒转基因表达。因此，我们建立了一种新型的慢病毒MMB技术，其在定点血管基因治疗方面具有巨大潜力。
