Use of mannosylated cationic liposomes/ immunostimulatory CpG DNA complex for effective inhibition of peritoneal dissemination in mice

Abstract

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. 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. 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. The results obtained suggest that i.p. administered Man/CpG DNA lipoplex can be used for efficient immunotherapy to combat peritoneal dissemination.