Impact of polyplex micelles installed with cyclic RGD peptide as ligand on gene delivery to vascular lesions
Impact of polyplex micelles installed with cyclic RGD peptide as ligand on gene delivery to vascular lesions
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DOI：
10.1038/gt.2011.74
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发表时间：
2012-01-01
期刊：
影响因子：
5.1
通讯作者：
Miyata, T.
中科院分区：
文献类型：
--
作者：
Kagaya, H.;Oba, M.;Miyata, T.
基因治疗有望为难治性血管疾病的治疗开辟新的策略，因此需要开发适合血管病变的基因载体。为了以非病毒方法实现这一要求，将环（RGDfK）肽（cRGD）引入嵌段共聚物，聚（乙二醇）-嵌段多阳离子携带乙二胺单元（PEG-PAsp(DET)）。cRGD识别在血管病变中大量表达的α (v) β(3)和α (v) β(5)整合素。cRGD-PEG-PAsp(DET) （cRGD-PEG-PAsp(DET)）通过与质粒DNA （pDNA）络合形成多聚胶束，与PEG-PAsp（DET）胶束相比，cRGD-PEG-PAsp（DET）胶束在内皮细胞和血管平滑肌细胞中的基因表达和细胞摄取效率显著提高。细胞内对pDNA的追踪表明，cRGD-PEG-PAsp（DET）胶束通过小泡介导的内吞作用被内化，这与避免溶酶体降解的途径有关，PEG-PAsp（DET）胶束通过网格蛋白介导的内吞作用被转运到酸性内体和溶酶体。此外，对新生内膜病变大鼠颈动脉的体内评估显示，cRGD-PEG-PAsp（DET）胶束实现了基因的持续表达，而PEG-PAsp（DET）胶束促进了基因的快速但短暂的表达。这些发现表明，将cRGD引入到多聚胶束中可能会为基因转移创造新的有用功能，并有助于建立有效的血管疾病基因治疗方法。基因治疗（2012）19,61-69；doi: 10.1038 / gt.2011.74;2011年6月9日在线发布
Gene therapy is expected to open a new strategy for the treatment of refractory vascular diseases, so the development of appropriate gene vectors for vascular lesions is needed. To realize this requirement with a non-viral approach, cyclo(RGDfK) peptide (cRGD) was introduced to block copolymer, poly(ethylene glycol)-block-polycation carrying ethylenediamine units (PEG-PAsp(DET)). cRGD recognizes alpha(v)beta(3) and alpha(v)beta(5) integrins, which are abundantly expressed in vascular lesions. cRGD-conjugated PEG-PAsp(DET) (cRGD-PEG-PAsp(DET)) formed polyplex micelles through complexation with plasmid DNA (pDNA) and the cRGD-PEG-PAsp(DET) micelles achieved significantly more efficient gene expression and cellular uptake as compared with PEG-PAsp(DET) micelles in endothelial cells and vascular smooth muscle cells. Intracellular tracking of pDNA showed that cRGD-PEG-PAsp(DET) micelles were internalized via caveolae-mediated endocytosis, which is associated with a pathway avoiding lysosomal degradation and that, PEG-PAsp(DET) micelles were transported to acidic endosomes and lysosomes via clathrin-mediated endocytosis. Further, in vivo evaluation in rat carotid artery with a neointimal lesion revealed that cRGD-PEG-PAsp(DET) micelles realized sustained gene expression, whereas PEG-PAsp(DET) micelles facilitated rapid, but transient gene expression. These findings suggest that introduction of cRGD to polyplex micelles might create novel and useful functions for gene transfer and contribute to the establishment of efficient gene therapy for vascular diseases. Gene Therapy (2012) 19, 61-69; doi:10.1038/gt.2011.74; published online 9 June 2011