Soluble Flt-1 gene delivery using PEI-g-PEG-RGD conjugate for anti-angiogenesis
Soluble Flt-1 gene delivery using PEI-g-PEG-RGD conjugate for anti-angiogenesis
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DOI：
10.1016/j.jconrel.2005.04.016
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发表时间：
2005-08-18
影响因子：
10.8
通讯作者：
Kim, SW
中科院分区：
文献类型：
--
作者：
Kim, WJ;Yockman, JW;Kim, SW
血管内皮生长因子（VEGF）是一种对血管内皮细胞特异性的强效血管生成分子，在大多数肿瘤中过表达，并与肿瘤生长和转移密切相关。已经显示，VEGF受体Flt-1（sFIt-1）的可溶性片段通过其针对VEGF的拮抗剂活性而具有抗血管生成性质。在本研究中，我们证明了通过内皮细胞靶向的非病毒基因递送稳定表达sFIt-1抑制内皮细胞的血管生成。通过将α v β 3/α v β 5整联蛋白结合的RGD肽ACDCRGDCFC（单字母氨基酸代码）通过亲水性聚乙二醇（PEG）间隔基掺入阳离子聚合物聚乙烯亚胺（PEI）中，开发了靶向聚合物基因递送系统PEI-g-PEG-RGD。用内皮细胞增殖试验对编码sFIT-1/载体复合物的治疗基因进行功能分析。sFlt-1基因与PEI-g-PEG-RGD偶联物的复合物能有效抑制培养的内皮细胞的增殖，表明sFlt-1基因的表达主要与外源性VEGF结合，并阻断了VEGF与全长Flt-1受体的结合。这些结果表明，靶向基因载体和sFlt-1的组合具有成为抗血管生成基因治疗癌症的有效工具的潜力。(c)2005 Elsevier B. V.保留所有权利。
Vascular endothelial growth factor (VEGF), a potent angiogenic molecule specific for vascular endothelial cells, is overexpressed in most tumors and closely associated with tumor growth and metastasis. It has been shown that a soluble fragment of VEGF receptor Flt-1 (sFIt-1) has anti-angiogenic properties by way of its antagonist activity against VEGF. In the present study, we demonstrated that the stable expression of sFIt-1 by endothelial cell targeted non-viral gene delivery inhibited the angiogenesis of endothelial cells. A targeted polymeric gene delivery system, PEI-g-PEG-RGD, was developed by incorporating the alpha v beta 3/alpha v beta 5 integrin-binding RGD peptide, ACDCRGDCFC (single-letter amino acid code), into the cationic polymer, polyethylenimine (PEI) via a hydrophilic polyethylene glycol (PEG) spacer. The functional analysis of therapeutic gene encoding sFIt-1/carrier complex was performed with an endothelial cell proliferation assay. The complex of sFlt-1 gene with PEI-g-PEG-RGD conjugate efficiently inhibited the proliferation of cultured endothelial cells, representing that expressed sFIt-1 predominantly bound to exogenous VEGF and blocked the binding of VEGF to the full-length Flt-1 receptor. These findings suggest that the combination of targeted gene carrier and sFlt-1 possesses the potential to be an efficient tool for the anti-angiogenic gene therapy to treat cancer. (c) 2005 Elsevier B.V. All rights reserved.