Department of Chemical and Biological Engineering, University of Wisconsin - Madison, Madison, WI 53706, USA.
Biomaterials. 2013 Jan;34(1):226-36. doi: 10.1016/j.biomaterials.2012.09.010. Epub 2012 Oct 13.
New therapeutic approaches that eliminate or reduce the occurrence of intimal hyperplasia following balloon angioplasty could improve the efficacy of vascular interventions and improve the quality of life of patients suffering from vascular diseases. Here, we report that treatment of arteries using catheter balloons coated with thin polyelectrolyte-based films ('polyelectrolyte multilayers', PEMs) can substantially reduce intimal hyperplasia in an in vivo rat model of vascular injury. We used a layer-by-layer (LbL) process to coat the surfaces of inflatable catheter balloons with PEMs composed of nanolayers of a cationic poly(β-amino ester) (polymer 1) and plasmid DNA (pPKCδ) encoding the δ isoform of protein kinase C (PKCδ), a regulator of apoptosis and other cell processes that has been demonstrated to reduce intimal hyperplasia in injured arterial tissue when administered via perfusion using viral vectors. Insertion of balloons coated with polymer 1/pPKCδ multilayers into injured arteries for 20 min resulted in local transfer of DNA and elevated levels of PKCδ expression in the media of treated tissue three days after delivery. IFC and IHC analysis revealed these levels of expression to promote downstream cellular processes associated with up-regulation of apoptosis. Analysis of arterial tissue 14 days after treatment revealed polymer 1/pPKCδ-coated balloons to reduce the occurrence of intimal hyperplasia by ~60% compared to balloons coated with films containing empty plasmid vectors. Our results demonstrate the potential therapeutic value of this nanotechnology-based approach to local gene delivery in the clinically important context of balloon-mediated vascular interventions. These PEM-based methods could also prove useful for other in vivo applications that require short-term, surface-mediated transfer of plasmid DNA.
新的治疗方法可以消除或减少球囊血管成形术后内膜增生的发生，从而提高血管介入的疗效，改善血管疾病患者的生活质量。在这里，我们报告说，用涂有薄聚电解质基薄膜（“聚电解质多层膜，PEMs）的导管球囊治疗动脉，可以显著减少血管损伤的体内大鼠模型中的内膜增生。我们使用层层（LbL）工艺将由阳离子聚（β-氨基酯）（聚合物 1）和编码蛋白激酶 C（PKCδ）δ同工型的质粒 DNA（pPKCδ）的纳米层组成的 PEM 涂覆在可充气导管球囊的表面上，PKCδ是一种调节细胞凋亡和其他细胞过程的调节剂，当通过病毒载体灌注给药时，已证明其可减少损伤动脉组织中的内膜增生。将涂有聚合物 1/pPKCδ多层膜的球囊插入损伤的动脉中 20 分钟，可导致在给药后 3 天处理组织的中膜中局部转移 DNA 和 PKCδ表达水平升高。IFC 和 IHC 分析显示，这些表达水平促进了与细胞凋亡上调相关的下游细胞过程。治疗后 14 天对动脉组织进行分析表明，与涂有含有空质粒载体的薄膜的球囊相比，聚合物 1/pPKCδ 涂层球囊可将内膜增生的发生率降低约 60%。我们的结果表明，在球囊介导的血管介入的临床重要背景下，这种基于纳米技术的局部基因传递方法具有潜在的治疗价值。这些基于 PEM 的方法对于其他需要短期表面介导的质粒 DNA 转移的体内应用也可能证明是有用的。
