Antiangiogenic gene therapy of experimental pancreatic tumor by sFlt-1 plasmid DNA carried by RGD-modified crosslinked polyplex micelles.
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.
Vachutinsky
Yelena
Y
Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan.
Oba
Makoto
M
Miyata
Kanjiro
K
Hiki
Shigehiro
S
Kano
Mitsunobu R
MR
Nishiyama
Nobuhiro
N
Koyama
Hiroyuki
H
Miyazono
Kohei
K
Kataoka
Kazunori
K
D000818:Animals; D045744:Cell Line, Tumor; D003432:Cross-Linking Reagents / Q000737:chemistry; D004247:DNA / Q000008:administration & dosage* / Q000235:genetics; D005260:Female; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D007275:Injections, Intravenous; D008239:Lysine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D008823:Micelles; D055806:Microvessels / Q000187:drug effects / Q000648:ultrastructure; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D009842:Oligopeptides / Q000737:chemistry; D010190:Pancreatic Neoplasms / Q000098:blood supply / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000737:chemistry*; D010957:Plasmids / Q000008:administration & dosage / Q000235:genetics; D011092:Polyethylene Glycols / Q000138:chemical synthesis / Q000737:chemistry*; D011107:Polylysine / Q000737:chemistry; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013438:Sulfhydryl Compounds / Q000737:chemistry; D014162:Transfection; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics*
C099578:(O-methylpoly(ethylene glycol)-O'-succinyl)-N-epsilon-poly(L-lysine); D003432:Cross-Linking Reagents; D008823:Micelles; D009842:Oligopeptides; D010456:Peptides, Cyclic; D013438:Sulfhydryl Compounds; C524089:cyclo(RGDfK(CX-))-poly(ethylene glycol)-polylysine; D011107:Polylysine; D011092:Polyethylene Glycols; C047981:arginyl-glycyl-aspartic acid; D004247:DNA; D040281:Vascular Endothelial Growth Factor Receptor-1; D008239:Lysine