Use of mannosylated cationic liposomes/ immunostimulatory CpG DNA complex for effective inhibition of peritoneal dissemination in mice.
BACKGROUND
Immunotherapy using immunostimulatory CpG DNA could be a promising new therapeutic approach to combat refractory peritoneal dissemination. In the present study, we report the use of a mannosylated cationic liposomes/immunostimulatory CpG DNA complex (Man/CpG DNA lipoplex) for effective inhibition of peritoneal dissemination in mice.


METHODS
The immune response characteristics of the Man/CpG DNA lipoplex were evaluated by measuring tumor necrosis factor (TNF)-alpha production using primary cultured mouse peritoneal macrophages. Subsequently, Man/CpG DNA lipoplex was administered intraperitoneally (i.p.) to peritoneal dissemination model mice, and the number of tumor cells (colon26/Luc) was quantitatively evaluated by measuring luciferase activity. The effect on survival time of the Man/CpG DNA lipoplex was also investigated. The serum transaminase levels of mice receiving i.p. Man/CpG DNA lipoplex treatment were measured to evaluate systemic toxicity.


RESULTS
The Man/CpG DNA lipoplex induced higher TNF-alpha production from macrophages than CpG DNA complexed with conventional cationic liposomes and galactosylated cationic liposomes (Bare/CpG DNA lipoplex and Gal/CpG DNA lipoplex), suggesting mannose receptor-mediated CpG DNA transfer. Intraperitoneal administration of Man/CpG DNA lipoplex inhibited the proliferation of tumor cells in the greater omentum and the mesentery more efficiently than Bare/CpG DNA lipoplex and Gal/CpG DNA lipoplex. Furthermore, the survival time of the peritoneal dissemination model mice was prolonged by i.p. administration of Man/CpG DNA lipoplex. The serum transaminase levels of mice receiving i.p. Man/CpG DNA lipoplex were found to be the same as those of untreated mice.


CONCLUSIONS
The results obtained suggest that i.p. administered Man/CpG DNA lipoplex can be used for efficient immunotherapy to combat peritoneal dissemination.
Kuramoto
Yukari
Y
Department of Drug Delivery Research, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan.
Kawakami
Shigeru
S
Zhou
Shuwen
S
Fukuda
Kyouichi
K
Yamashita
Fumiyoshi
F
Hashida
Mitsuru
M
D000818:Animals; D045744:Cell Line, Tumor; D004247:DNA / Q000627:therapeutic use*; D005260:Female; D007167:Immunotherapy; D016753:Interleukin-10 / Q000096:biosynthesis; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008813:Mice, Inbred ICR; D010316:Particle Size; D010534:Peritoneal Neoplasms / Q000188:drug therapy* / Q000556:secondary*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D004247:DNA