Antiangiogenic gene therapy of experimental pancreatic tumor by sFlt-1 plasmid DNA carried by RGD-modified crosslinked polyplex micelles.

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.

• Authors: Yelena Vachutinsky, Makoto Oba, Kanjiro Miyata, Shigehiro Hiki, Mitsunobu R Kano, Nobuhiro Nishiyama, Hiroyuki Koyama, Kohei Miyazono, Kazunori Kataoka
• Journal: Journal of controlled release : official journal of the Controlled Release Society (J Control Release) Vol. 149 Issue 1 Pg. 51-7 (Jan 05 2011) ISSN: 1873-4995 [Electronic] Netherlands
• PMID: 20138936 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2010 Elsevier B.V. All rights reserved.

Chemical References

• (O-methylpoly(ethylene glycol)-O'-succinyl)-N-epsilon-poly(L-lysine)
• Cross-Linking Reagents
• Micelles
• Oligopeptides
• Peptides, Cyclic
• Sulfhydryl Compounds
• cyclo(RGDfK(CX-))-poly(ethylene glycol)-polylysine
• Polylysine
• Polyethylene Glycols
• arginyl-glycyl-aspartic acid
• DNA
• Vascular Endothelial Growth Factor Receptor-1
• Lysine

Topics

• Animals
• Cell Line, Tumor
• Cross-Linking Reagents (chemistry)
• DNA (administration & dosage, genetics)
• Female
• Gene Transfer Techniques
• Genetic Therapy
• Injections, Intravenous
• Lysine (analogs & derivatives, chemical synthesis, chemistry)
• Mice
• Mice, Inbred BALB C
• Micelles
• Microvessels (drug effects, ultrastructure)
• Neoplasm Transplantation
• Neovascularization, Pathologic (genetics, pathology, prevention & control)
• Oligopeptides (chemistry)
• Pancreatic Neoplasms (blood supply, genetics, pathology, therapy)
• Peptides, Cyclic (chemical synthesis, chemistry)
• Plasmids (administration & dosage, genetics)
• Polyethylene Glycols (chemical synthesis, chemistry)
• Polylysine (chemistry)
• Reverse Transcriptase Polymerase Chain Reaction
• Sulfhydryl Compounds (chemistry)
• Transfection
• Vascular Endothelial Growth Factor Receptor-1 (genetics)