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

• Published in: Journal of controlled release 2013-05, Vol.167 (3), p.238-247
• Main Authors: Ohgidani, Masahiro, Furugaki, Koichi, Shinkai, Kentaro, Kunisawa, Yumi, Itaka, Keiji, Kataoka, Kazunori, Nakano, Kenji
• Format: Article
• Language: English
• Subjects: Animal models; Animals; bioluminescence; Block/homo polyplex micelle; blood serum; Cell Line, Tumor; composite polymers; Cynomolgus; DNA - administration & dosage; Female; fibrinogen; gene expression; Gene Expression Regulation, Neoplastic; gene therapy; Genetic Therapy - methods; Granulocyte macrophage colony stimulating factor; Granulocyte-Macrophage Colony-Stimulating Factor - genetics; Humans; image analysis; immunity; Immunogene therapy; Injections, Intraperitoneal; Intraperitoneal administration; intraperitoneal injection; Killer Cells, Natural - immunology; Liver - metabolism; luciferase; Lymph Nodes - metabolism; Macaca fascicularis; Mice; Mice, Inbred BALB C; Mice, Nude; Micelles; monkeys; natural killer cells; pancreatic neoplasms; Pancreatic Neoplasms - immunology; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - therapy; Peritoneal dissemination; polyethylene glycol; Polyethylene Glycols - chemistry; Proteins - chemistry; RNA, Messenger - metabolism; Safety evaluation test in cynomolgus monkeys; Spleen - metabolism; survival rate
• ISSN: 0168-3659; 1873-4995
• DOI: 10.1016/j.jconrel.2013.02.006

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 24h 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. [Display omitted]