title: Block/homo polyplex micelle-based GM-CSF gene therapy via intraperitoneal administration elicits antitumor immunity against peritoneal dissemination and exhibits safety potentials in mice and cynomolgus monkeys.
abstract: A block/homo-mixed polyplex micelle, comprising of cationic homo polymer: poly{N'-[N-(2-aminoethyl)-2-aminoethyl]aspartamide} P[Asp(DET)] and block copolymer: polyethylene glycol (PEG)-b-P[Asp(DET)], has been reported to exhibit the efficient transgene expression in vivo by intratracheal and systemic administration. In the present study, we investigated the potential of immunogene therapy by intraperitoneal (i.p.) administration of block/homo polyplex micelles for peritoneal dissemination. For evaluation of transgene expression in vivo, block/homo polyplex micelles showed 12-fold higher level in luciferase expression evaluated by bioluminescence imaging system at 24 h after the i.p. administration compared with block polyplex micelles composed with only PEG-b-P[Asp(DET)] in nude mice bearing peritoneal dissemination. The distribution of block/homo polyplex micelles and intracellular uptake of pDNA was observed in tumor nodules. The tumor growth and the prolonged survival rate for the mice harboring disseminated pancreatic cancer more significantly compared with the mock. The antitumor effect of GM-CSF gene therapy was mediated via the activation of natural killer cells. For safety evaluation, block/homo polyplex micelles indicated almost no adverse events for patho-physical findings and blood examinations in mice and cynomolgus monkeys, although slight increases in serum fibrinogen were observed in the monkey model. In conclusion, block/homo polyplex micelle-based immunogene therapy via i.p. administration may be a safe and effective approach for suppressing intractable peritoneal dissemination.
authors: Innovation Center for Medical Redox Navigation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors: Masahiro
authors: M
authors: Ohgidani
authors: Koichi
authors: K
authors: Furugaki
authors: Kentaro
authors: K
authors: Shinkai
authors: Yumi
authors: Y
authors: Kunisawa
authors: Keiji
authors: K
authors: Itaka
authors: Kazunori
authors: K
authors: Kataoka
authors: Kenji
authors: K
authors: Nakano
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004247:DNA / Q000008:administration & dosage*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D015316:Genetic Therapy / Q000379:methods*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics*; D006801:Humans; D007274:Injections, Intraperitoneal; D007694:Killer Cells, Natural / Q000276:immunology; D008099:Liver / Q000378:metabolism; D008198:Lymph Nodes / Q000378:metabolism; D008252:Macaca fascicularis; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008823:Micelles; D010190:Pancreatic Neoplasms / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D011092:Polyethylene Glycols / Q000737:chemistry; D011506:Proteins / Q000737:chemistry; D012333:RNA, Messenger / Q000378:metabolism; D013154:Spleen / Q000378:metabolism
chemical_list: D008823:Micelles; D011506:Proteins; D012333:RNA, Messenger; C571441:poly(ethylene glycol)-poly(N'-(N-(2-aminoethyl)-2-aminoethyl)aspartamide) block copolymer; D011092:Polyethylene Glycols; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D004247:DNA