Biocompatible micellar nanovectors achieve efficient gene transfer to vascular lesions without cytotoxicity and thrombus formation
Biocompatible micellar nanovectors achieve efficient gene transfer to vascular lesions without cytotoxicity and thrombus formation
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DOI：
10.1038/sj.gt.3302945
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发表时间：
2007-07-01
期刊：
影响因子：
5.1
通讯作者：
Kataoka, K.
中科院分区：
文献类型：
--
作者：
Akagi, D.;Oba, M.;Kataoka, K.
基因治疗是一种很有前途的治疗血管疾病的方法，需要合适的基因载体，具有高的基因转移效率、良好的生物相容性和低的细胞毒性。为了满足这些要求的方法的非病毒载体，一种新的嵌段共聚物，聚（乙二醇）（PEG）-嵌段聚阳离子，携带乙二胺单元的侧链（PEG-b-P[Asp（DET）]）的制备。PEG-b-P[Asp（DET）]通过与质粒DNA（pDNA）形成聚离子复合物而形成聚复合物胶束。PEG-b-P[Asp（DET）]复合物胶束在体外对血管平滑肌细胞显示出高效的基因表达和低的细胞毒性。它还显示出与血液成分的相互作用减少，提供了通过血管腔进行基因递送的可行性。为了评价体内基因转移对血管病变的效率，通过血管内方法将PEG-b-P[Asp（DET）]胶束滴注到具有新生内膜的兔颈动脉中，并评估报告基因在血管病变中的表达。使用来自均聚物P[Asp（DET）]和支链聚乙烯亚胺（BPEI）的聚合复合物作为对照。最后，只有复合物胶束显示出明显的基因转移到血管病变中，而没有任何血管血栓闭塞，这与经常显示血栓闭塞的BPEI和P[Asp（DET）]复合物形成强烈对比。这些发现表明PEG-b-P[Asp（DET）]复合物胶束可能具有作为用于治疗血管疾病的非病毒载体的有希望的潜力。
Gene therapy, a promising treatment for vascular disease, requires appropriate gene vectors with high gene transfer efficiency, good biocompatibility and low cytotoxicity. To satisfy these requirements from the approach of nonviral vectors, a novel block copolymer, poly(ethylene glycol) (PEG)-block-polycation, carrying ethylenediamine units in the side chain (PEG-b-P[Asp(DET)]) was prepared. PEG-b-P[Asp(DET)] formed a polyplex micelle through polyion complex formation with plasmid DNA (pDNA). The PEG-b-P[Asp(DET)] polyplex micelle showed efficient gene expression with low cytotoxicity against vascular smooth muscle cells in vitro. It also showed reduced interactions with blood components, offering its feasibility of gene delivery via the vessel lumen. To evaluate in vivo gene transfer efficiency for vascular lesions, PEG-b-P[Asp(DET)] micelle was instilled into rabbit carotid artery with neointima by an intravascular method, and expression of the reporter gene in vascular lesions was assessed. Polyplexes from homopolymer P[Asp(DET)] and branched polyethyleneimine (BPEI) were used as controls. Ultimately, only the polyplex micelle showed appreciable gene transfer into vascular lesions without any vessel occlusion by thrombus, which was in strong contrast to BPEI and P[Asp(DET)] polyplexes which frequently showed occlusion with thrombus. These findings suggest that the PEG-b-P[Asp(DET)] polyplex micelle may have promising potential as a nonviral vector for the treatment of vascular diseases.