Soluble Flt-1 gene delivery using PEI-g-PEG-RGD conjugate for anti-angiogenesis

被引:116
作者
Kim, WJ
Yockman, JW
Lee, M
Jeong, JH
Kim, YH
Kim, SW
机构
[1] Univ Utah, Ctr Controlled Chem Delivery, Dept Pharmaceut & Pharmaceut Chem, Salt Lake City, UT 84112 USA
[2] Hanyang Univ, Coll Engn, Dept Bioengn, Seoul 133791, South Korea
关键词
gene therapy; anti-angiogenesis; RGD peptide; soluble Flt-1; VEGF;
D O I
10.1016/j.jconrel.2005.04.016
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
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.
引用
收藏
页码:224 / 234
页数:11
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