title: Effective transgene expression without toxicity by intraperitoneal administration of PEG-detachable polyplex micelles in mice with peritoneal dissemination.
abstract: Block copolymer of poly(ethylene glycol)-block-poly{N-[N-(2-aminoethyl)-2-aminoethyl]aspartamide} (PEG-P[Asp(DET)]) has been originally introduced as a promising gene carrier by forming a nanomicelle with plasmid DNA. In this study, the polyplex micelle of PEG-SS-P[Asp(DET)], which disulfide linkage (SS) between PEG and cationic polymer can detach the surrounding PEG chains upon intracellular reduction, was firstly evaluated with respect to in vivo transduction efficiency and toxicity in comparison to that of PEG-P[Asp(DET)] in peritoneally disseminated cancer model. Intraperitoneal (i.p.) administration of PEG-SS-P[Asp(DET)] polyplex micelles showed a higher (P<0.05) transgene expression compared with PEG-P[Asp(DET)] in tumors. In contrast, the delivered distribution of the micelles was not different between the two polyplex micelles. PEG-SS-P[Asp(DET)] micelle encapsulating human tumor necrosis factor α (hTNF-α) gene exhibits a higher antitumor efficacy against disseminated cancer compared with PEG-P[Asp(DET)] or saline control. No hepatic and renal toxicities were observed by the administration of polyplex micelles. In conclusion, PEG-detachable polyplex micelles may represent an advantage in gene transduction in vivo over PEG-undetachable polyplex micelles after i.p. administration for peritoneal dissemination of cancer.
authors.affiliation: Innovation Center for Medical Redox Navigation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Fukuoka 812-8582, Japan.
authors.forename: Michiaki
authors.initials: M
authors.lastname: Kumagai
authors.forename: Shinya
authors.initials: S
authors.lastname: Shimoda
authors.forename: Rie
authors.initials: R
authors.lastname: Wakabayashi
authors.forename: Yumi
authors.initials: Y
authors.lastname: Kunisawa
authors.forename: Takehiko
authors.initials: T
authors.lastname: Ishii
authors.forename: Kensuke
authors.initials: K
authors.lastname: Osada
authors.forename: Keiji
authors.initials: K
authors.lastname: Itaka
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Nishiyama
authors.forename: Kazunori
authors.initials: K
authors.lastname: Kataoka
authors.forename: Kenji
authors.initials: K
authors.lastname: Nakano
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D015316:Genetic Therapy / Q000379:methods; D006801:Humans; D007274:Injections, Intraperitoneal; D008099:Liver / Q000378:metabolism; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008823:Micelles; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000378:metabolism / Q000628:therapy*; D011092:Polyethylene Glycols / Q000008:administration & dosage* / Q000737:chemistry; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage* / Q000235:genetics* / Q000378:metabolism; D013154:Spleen / Q000378:metabolism; D013388:Succinimides / Q000008:administration & dosage* / Q000737:chemistry; D019076:Transgenes / Q000235:genetics
chemical_list: D008823:Micelles; C530799:RGD4C-TNF fusion protein; D011993:Recombinant Fusion Proteins; D013388:Succinimides; D011092:Polyethylene Glycols; C050761:polyethylene glycol bis(succinimidyl succinate); D008156:Luciferases