Soluble Flt-1 gene delivery using PEI-g-PEG-RGD conjugate for anti-angiogenesis.
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 (sFlt-1) has anti-angiogenic properties by way of its antagonist activity against VEGF. In the present study, we demonstrated that the stable expression of sFlt-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 alphanubeta3/alphanubeta5 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 sFlt-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 sFlt-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.
Kim
Won Jong
WJ
Center for Controlled Chemical Delivery, Department of Pharmaceutics and Pharmaceutical Chemistry, 30 S 2000 E RM 201, University of Utah, Salt Lake City, UT 84112-5820, USA.
Yockman
James W
JW
Lee
Minhyung
M
Jeong
Ji Hoon
JH
Kim
Yong-Hee
YH
Kim
Sung Wan
SW
D020533:Angiogenesis Inhibitors / Q000008:administration & dosage* / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004337:Drug Carriers; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D009842:Oligopeptides / Q000737:chemistry; D010456:Peptides, Cyclic / Q000008:administration & dosage* / Q000138:chemical synthesis; D010957:Plasmids; D011092:Polyethylene Glycols / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000737:chemistry; D011094:Polyethyleneimine / Q000737:chemistry; D014162:Transfection / Q000379:methods*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000008:administration & dosage* / Q000235:genetics
D020533:Angiogenesis Inhibitors; D004337:Drug Carriers; D009842:Oligopeptides; C507107:PEI-g-PEG-RGD; D010456:Peptides, Cyclic; D042461:Vascular Endothelial Growth Factor A; D011092:Polyethylene Glycols; C047981:arginyl-glycyl-aspartic acid; D011094:Polyethyleneimine; C501162:FLT1 protein, human; D040281:Vascular Endothelial Growth Factor Receptor-1