Abstract
Disulfide crosslinked polyplex micelles with RGD peptides were formed through ion complexation of thiolated c(RGDfK)-poly(ethylene glycol)-block-poly(L-lysine) (c(RGDfK)-PEG-P(Lys-SH)) and plasmid DNA encoding sFlt-1 and tested for their therapeutic effect in BxPC3 pancreatic adenocarcinoma tumor bearing mice. These micelles, systemically injected, demonstrated significant inhibition of tumor growth up to day 18, as a result of the antiangiogenic effect that was confirmed by vascular density measurements. Significant therapeutic activity of the 15% crosslinked micelle (c(RGDfK)-PEG-P(Lys-SH15)) was achieved by combined effect of increased tumor accumulation, interaction with endothelial cells and enhanced intracellular uptake through receptor-mediated endocytosis. These results suggest that RGD targeted crosslinked polyplex micelles can be effective plasmid DNA carriers for antiangiogenic gene therapy.
Copyright © 2010 Elsevier B.V. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cell Line, Tumor
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Cross-Linking Reagents / chemistry
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DNA / administration & dosage*
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DNA / genetics
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Female
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Gene Transfer Techniques*
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Genetic Therapy*
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Injections, Intravenous
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Lysine / analogs & derivatives*
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Lysine / chemical synthesis
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Lysine / chemistry
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Mice
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Mice, Inbred BALB C
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Micelles
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Microvessels / drug effects
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Microvessels / ultrastructure
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Neoplasm Transplantation
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Neovascularization, Pathologic / genetics
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Neovascularization, Pathologic / pathology
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Neovascularization, Pathologic / prevention & control*
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Oligopeptides / chemistry
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Pancreatic Neoplasms / blood supply
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Pancreatic Neoplasms / genetics
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Pancreatic Neoplasms / pathology
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Pancreatic Neoplasms / therapy*
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Peptides, Cyclic / chemical synthesis
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Peptides, Cyclic / chemistry*
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Plasmids / administration & dosage
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Plasmids / genetics
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Polyethylene Glycols / chemical synthesis
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Polyethylene Glycols / chemistry*
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Polylysine / chemistry
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Reverse Transcriptase Polymerase Chain Reaction
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Sulfhydryl Compounds / chemistry
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Transfection
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Vascular Endothelial Growth Factor Receptor-1 / genetics*
Substances
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(O-methylpoly(ethylene glycol)-O'-succinyl)-N-epsilon-poly(L-lysine)
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Cross-Linking Reagents
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Micelles
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Oligopeptides
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Peptides, Cyclic
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Sulfhydryl Compounds
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cyclo(RGDfK(CX-))-poly(ethylene glycol)-polylysine
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Polylysine
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Polyethylene Glycols
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arginyl-glycyl-aspartic acid
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DNA
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Vascular Endothelial Growth Factor Receptor-1
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Lysine