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.
Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan.
Yelena
Y
Vachutinsky
Makoto
M
Oba
Kanjiro
K
Miyata
Shigehiro
S
Hiki
Mitsunobu R
MR
Kano
Nobuhiro
N
Nishiyama
Hiroyuki
H
Koyama
Kohei
K
Miyazono
Kazunori
K
Kataoka
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